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Sirtuin Biology in Cancer and Metabolic Disease: Cellular Pathways for Clinical Discovery
 0128224673, 9780128224670

Table of contents :
Title-page_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
Sirtuin Biology in Cancer and Metabolic Disease
Copyright_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
Copyright
Dedication_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
Dedication
Contents_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
Contents
List-of-contributors_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
List of contributors
About-the-editor_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
About the editor
Preface_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
Preface
Acknowledgment_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
Acknowledgment
Chapter-1---Sirtuins-in-metabolic-disease--innovat_2021_Sirtuin-Biology-in-C
1 Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide
Abbreviations
1.1 Noncommunicable diseases
1.2 Metabolic disorders
1.3 Novel therapeutic strategies with sirtuins for metabolic disease
1.4 Silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae)
1.5 SIRT1, metabolic function, and obesity
1.6 SIRT1 and AMP-activated protein kinase
1.7 SIRT1, mTOR, and metabolic disease
1.8 SIRT1, nicotinamide, and cellular metabolism
1.9 Future considerations
Acknowledgments
References
Chapter-2---Sirtuins-in-metabolic-and-epige_2021_Sirtuin-Biology-in-Cancer-a
2 Sirtuins in metabolic and epigenetic regulation of stem cells
2.1 Introduction
2.2 Stem cells and sirtuins
2.3 SIRT1 in stem cell biology
2.3.1 SIRT1 is important for normal embryogenesis and animal development
2.3.2 SIRT1 maintains pluripotent ESCs through multilevel mechanisms
2.3.3 SIRT1 is important for the maintenance of diverse ASC pools
2.3.4 SIRT1 is important in maintaining/promoting stemness and survival of CSCs
2.4 SIRT2 in stem cell biology
2.4.1 SIRT2 promotes differentiation of ESCs in vitro
2.4.2 SIRT2 promotes survival of CSCs
2.5 SIRT3 in stem cell biology
2.5.1 SIRT3 maintains the pool and regenerative capacity of HSCs during aging
2.6 SIRT6 in stem cell biology
2.6.1 SIRT6 epigenetically promotes proper lineage commitment of ESCs and animal development
2.6.2 SIRT6 controls regeneration and stress resistance in HSCs and mesenchymal stem cells
2.6.3 SIRT6 suppresses stemness of CSCs
2.7 SIRT7 in stem cell biology
2.7.1 SIRT7 regulates embryogenesis and life span through maintenance of genome stability
2.7.2 SIRT7 regulates quiescence and regenerative capacity of HSCs
2.8 Concluding remarks and future perspectives
References
Chapter-3---Sirtuins-and-metabolic-regulati_2021_Sirtuin-Biology-in-Cancer-a
3 Sirtuins and metabolic regulation: food and supplementation
3.1 Introduction
3.2 Tissue-specific sirtuin-modulated metabolic regulation
3.2.1 Liver
3.2.2 Adipose tissue
3.2.3 Heart and skeletal muscle
3.2.4 Kidneys
3.2.5 Pancreas
3.2.6 Brain
3.3 Nutrition as a therapeutic model for sirtuin regulation
3.3.1 Polyphenols
3.4 Resveratrol
3.5 Gallic acid
3.6 Nonresveratrol related sirtuin activators
3.7 Food and sirtuins
3.7.1 Mediterranean diet
3.7.2 Berberin
3.7.3 Green cardamom
3.7.4 Cocoa
3.7.5 Indole-3-carbinol
3.7.6 Xanthigen
3.8 Conclusion
References
Chapter-4---Sirtuins-in-diabetes-mellitus-_2021_Sirtuin-Biology-in-Cancer-an
4 Sirtuins in diabetes mellitus and diabetic kidney disease
4.1 Introduction
Part 1
4.2 Sirtuin 1 (SIRT1) in normal physiology
4.2.1 Major roles of SIRT1 in glucose metabolism
4.2.2 Major roles of SIRT1 in lipid metabolism
4.2.3 Major roles of SIRT3 in glucose metabolism and lipid metabolism
4.2.4 Major roles of SIRT4 in glucose and lipid metabolism
Part 2
4.3 Diabetes mellitus and sirtuins
4.3.1 The roles of sirtuins in the pathogenesis of diabetes mellitus
4.3.2 Sirtuins and diabetic kidney disease
4.3.2.1 What are the effects of SIRT6 and SIRT7 in kidney?
4.3.3 The roles of SIRT1 in the glomerulus in diabetic kidney disease
4.3.3.1 Results from animal models of diabetes mellitus
4.3.3.2 Results from cell culture studies
4.3.4 The roles of SIRT1 in the tubulointerstitium in diabetic kidney disease
4.3.4.1 Results from animal models of diabetes mellitus
4.3.4.2 Results from cell culture studies
4.3.5 The roles of SIRT1 and autophagy in diabetes mellitus and diabetic kidney disease
4.3.6 The roles of SIRT1 and adenosine monophosphate-activated protein kinase pathway in diabetic kidney disease
4.3.7 The roles of SIRT1 and mTOR pathway in diabetic kidney disease
4.4 Hypertension and sirtuins
4.5 Novel treatment options in diabetes mellitus and diabetic kidney disease
4.6 Conclusion and future perspectives
References
Chapter-5---Sirtuins-and-mitochondria_2021_Sirtuin-Biology-in-Cancer-and-Met
5 Sirtuins and mitochondrial dysfunction
5.1 Sirtuins are nutrient sensors
5.2 Sirtuins and mitochondrial biogenesis
5.3 Sirtuins and mitochondrial metabolism
5.4 Sirtuins and mitochondrial dysfunction in human diseases
5.4.1 Diabetes and obesity
5.4.2 Cardiovascular diseases
5.4.3 Renal disease
5.4.4 Neurodegeneration
5.4.5 Aging
5.4.6 Tumorigenesis
5.5 Feasible clinical targets: posttranslational modifications of sirtuins regulate mitochondrial function
Acknowledgments
References
Chapter-6---Sirtuins-in-immunomet_2021_Sirtuin-Biology-in-Cancer-and-Metabol
6 Sirtuins in immunometabolism
6.1 Brief introduction of immunometabolism
6.2 Role of sirtuins in immunometabolism
6.2.1 SIRT1
6.2.1.1 SIRT1 in macrophage
6.2.1.2 SIRT1 in myeloid-derived suppressor cells
6.2.1.3 SIRT1 in dendritic cells
6.2.1.4 SIRT1 in T cells
6.2.2 SIRT2
6.2.3 SIRT3, SIRT4, and SIRT5
6.2.4 SIRT6
6.2.5 SIRT7
6.3 Conclusion and future considerations
References
Chapter-7---Mitochondrial-sirtuins-at-the-crossr_2021_Sirtuin-Biology-in-Can
7 Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation
Abbreviations
7.1 Introduction—advantages of possessing mitochondria
7.2 Mitochondrial sirtuins
7.3 Lipoylation of multienzymatic complexes is essential for mitochondrial metabolism
7.4 Alternative lipoylation and its metabolic consequences
7.5 Regulation of pyruvate dehydrogenase complex by mitochondrial sirtuins
7.6 Alpha ketoglutarate dehydrogenase complex regulates gene expression
7.7 Fluctuations of the intracellular concentration of organic acids has far-reaching implications
7.8 Ketogenic enzymes ACAT1 and HMGCS2 as substrates for Sirt3 and Sirt5
7.9 Antagonistic roles of mitochondrial sirtuins in fed and fasted state
7.10 The interplay between Sirt3 and isocitrate dehydrogenase in cancer cells
7.11 Tumor-suppressing and tumor-promoting activities of sirtuins in the context of glutamine and glucose metabolism
7.12 Sirtuins regulate iron–sulfur cluster assemblage
7.13 Mitochondrial fatty acid synthesis is linked to Fe–S cluster assembly and protein lipoylation—implications for cancer ...
7.14 Consequences of Fe–S cluster defects in cancer cells
7.15 Deoxyribonucleotide synthesis—toward the as yet unexplored areas of sirtuin research
7.16 Perspectives—evolutionary implications and new directions in cancer treatment
References
Chapter-8---Sirtuins-and-the-hallmar_2021_Sirtuin-Biology-in-Cancer-and-Meta
8 Sirtuins and the hallmarks of cancer
8.1 Introduction
8.2 Sirtuins in sustaining proliferative signaling and evading growth suppressors
8.3 Sirtuins and resisting cell death
8.4 Sirtuins in tumor-promoting inflammation and immune system function
8.5 Sirtuins in angiogenesis
8.6 Sirtuins in invasion and metastasis
8.7 Sirtuins in genome instability and replicative immortality
8.8 Sirtuins in reprogramming energy metabolism
8.9 Sirtuins and cancer therapy
8.10 Concluding remarks
References
Chapter-9---The-bifunctional-roles-of-sirtuins_2021_Sirtuin-Biology-in-Cance
9 The bifunctional roles of sirtuins and their therapeutic potential in cancer
9.1 The mammalian sirtuins
9.1.1 SIRT1
9.1.1.1 SIRT1 as a tumor suppressor
9.1.1.2 SIRT1 as an oncoprotein
9.1.2 SIRT2
9.1.2.1 SIRT2 as a tumor suppressor
9.1.2.2 SIRT2 as an oncoprotein
9.1.3 SIRT3
9.1.3.1 SIRT3 as a tumor suppressor
9.1.3.2 SIRT3 as an oncoprotein
9.1.4 SIRT4
9.1.4.1 SIRT4 as a tumor suppressor
9.1.4.2 SIRT4 as an oncoprotein
9.1.5 SIRT5
9.1.5.1 SIRT5 as a tumor suppressor
9.1.5.2 SIRT5 as an oncoprotein
9.1.6 SIRT6
9.1.6.1 SIRT6 as tumor suppressor
9.1.6.2 SIRT6 as an oncoprotein
9.1.7 SIRT7
9.1.7.1 SIRT7 as a tumor suppressor
9.1.7.2 SIRT7 as an oncoprotein
9.2 Sirtuin modulators
9.2.1 Sirtuin inhibitors
9.2.1.1 Nicotinamide and its analogues
9.2.1.2 β-Naphthol-containing inhibitors
9.2.1.3 Indole derivatives
9.2.1.4 Thioacyllysine-containing compounds
9.2.1.5 Tenovin
9.2.1.6 Suramin
9.2.1.7 Other SIRTi
9.2.1.7.1 AGK2
9.2.1.7.2 MHY2256
9.2.1.7.3 SirReal2
9.2.1.7.4 MC2494
9.2.1.7.5 Toxoflavin
9.2.2 Sirtuin activators
9.3 Conclusion and future perspectives
Acknowledgment
References
Chapter-10---Sirtuins-and-next-generation-hallmark_2021_Sirtuin-Biology-in-C
10 Sirtuins and next generation hallmarks of cancer: cellular energetics and tumor promoting inflammation
10.1 Introduction: an overview of sirtuins involvement in inflammation and cancer metabolism
10.2 Nuclear and cytosolic sirtuins involvement in metabolism of cancer and inflammatory cells
10.2.1 SIRT1
10.2.2 SIRT2
10.2.3 SIRT6
10.2.4 SIRT7
10.3 Mitochondrial sirtuins
10.3.1 SIRT3
10.3.2 SIRT4
10.3.3 SIRT5
10.4 Sirtuins indeed link metabolism, inflammation, and cancer?
10.5 Conclusions and perspectives
References
Chapter-11---Sirtuins-and-cellular-meta_2021_Sirtuin-Biology-in-Cancer-and-M
11 Sirtuins and cellular metabolism in cancers
11.1 The metabolic characteristics of cancers
11.1.1 Glucose metabolism in cancers
11.1.2 Lipometabolism in cancers
11.1.3 Other kinds of metabolism in cancers
11.2 The regulatory modes of sirtuins in controlling cellular metabolism
11.3 Direct epigenetic control of cellular metabolism by sirtuins
11.3.1 Direct epigenetic control of glucometabolism by sirtuins
11.3.2 Direct epigenetic control of lipometabolism by sirtuins
11.3.3 Direct epigenetic control of amino acid metabolism by sirtuins
11.4 Direct posttranslational control of cellular metabolism by sirtuins
11.4.1 Direct posttranslational control of glycolytic enzymes and transporters by sirtuins
11.4.2 Direct posttranslational control of OXPHOS by sirtuins
11.4.3 Direct posttranslational control of lipometabolism by sirtuins
11.4.4 Direct posttranslational control of amino acid metabolism by sirtuins
11.5 Indirect control of cellular metabolism by sirtuins
11.5.1 Indirect control of glycolysis by sirtuins
11.5.1.1 HIF-1/2
11.5.1.2 c-Myc
11.5.1.3 LKB1-AMPK
11.5.1.4 p53
11.5.1.5 Other
11.5.2 Indirect control of OXPHOS by sirtuins
11.5.2.1 PGC-1α
11.5.2.2 MnSOD
11.5.2.3 Drp1
11.5.2.4 GABPα/GABPβ complex
11.5.3 Indirect control of lipometabolism by sirtuins
11.5.3.1 PPARα/γ and PGC-1α
11.5.3.2 SREBP family
11.5.3.3 TR4/TAK1
11.5.3.4 PI3K-Akt
11.5.3.5 LKB1
11.5.4 Indirect control of amino acid metabolism by sirtuins
11.6 Conclusions
References
Chapter-12---Dual-role-of-sirtuins_2021_Sirtuin-Biology-in-Cancer-and-Metabo
12 Dual role of sirtuins in cancer
12.1 Introduction
12.2 Sirtuins and cancer metabolism
12.3 Sirtuins and oxidative damage
12.4 Sirtuins, genomic stability, and DNA repair
12.5 Sirtuins and metastasis
12.6 Sirtuins and cancer stem cells
12.7 Sirtuins and chemoresistance
12.8 Sirtuins: tumor suppressors or promoters?
References
Chapter-13---Sirtuin-signaling-in-hemat_2021_Sirtuin-Biology-in-Cancer-and-M
13 Sirtuin signaling in hematologic malignancies
Abbreviations
13.1 Introduction
13.2 Hematologic malignancies
13.2.1 The many facets of SIRT1 in cancer biology
13.2.2 Oncogenic roles of SIRT1
13.2.3 Tumor-suppressive roles of SIRT1
13.2.4 SIRT1 in hematologic malignancies
13.2.5 Closing thoughts on SIRT1
13.2.6 SIRT2 regulates genomic stability
13.2.7 SIRT3, the major mitochondrial deacetylase
13.2.8 The elusive SIRT4 regulates glutamine metabolism
13.2.9 SIRT5: the oncogenic desuccinylase
13.2.10 SIRT6 and the age-old Warburg effect
13.2.11 SIRT7 is an oncogene that promotes ribosome biogenesis and DNA repair
13.3 Sirtuins regulate pathways important for hematologic malignancies
13.3.1 MYC-driven hematologic malignancies
13.3.2 Sirtuins and the BCL-2 family of proteins
13.3.3 Sirtuins regulate NF-κB signaling
13.3.4 CD38, a major NADase, affects sirtuin activity
13.4 Therapeutic opportunities
13.5 Conclusions
References
Chapter-14---Impacts-of-sirtuin1-and-sirtu_2021_Sirtuin-Biology-in-Cancer-an
14 Impacts of sirtuin1 and sirtuin3 on oral carcinogenesis
14.1 Introduction
14.2 Overview of sirtuins
14.2.1 Sirtuin1
14.2.2 Sirtuin3
14.3 Involvement of sirtuins in oral cancer
14.3.1 Sirtuin1 and oral cancer
14.3.2 Sirtuin3 and oral cancer
14.4 Potential therapeutic implications of sirtuins in oral cancer
14.5 Concluding remarks
References
Index_2021_Sirtuin-Biology-in-Cancer-and-Metabolic-Disease
Index

Citation preview

SIRTUIN BIOLOGY IN CANCER AND METABOLIC DISEASE

SIRTUIN BIOLOGY IN CANCER AND METABOLIC DISEASE Cellular Pathways for Clinical Discovery Edited By

KENNETH MAIESE Biotechnology and Venture Capital Development, Office of Translational Alliances and Coordination, National Heart, Lung, and Blood Institute; Cellular and Molecular Signaling, New York, NY, United States

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-822467-0 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisitions Editor: Ana Claudia A. Garcia Editorial Project Manager: Timothy Bennett Production Project Manager: Omer Mukthar Cover Designer: Christian J. Bilbow Typeset by MPS Limited, Chennai, India

Dedication

To all our readers and to the never-ending drive in all of us to reject the “status quo,” embrace innovation, and carry forward novel avenues of discovery that looks forward and inspires advanced treatments for cancer and metabolic diseases.

Contents

List of contributors About the editor Preface Acknowledgment

2.8 Concluding remarks and future perspectives References

xi xiii xv xvii

3. Sirtuins and metabolic regulation: food and supplementation SE´RGIO HENRIQUE SOUSA SANTOS, VICTOR HUGO DANTAS ˜ ES, JANAINA RIBEIRO OLIVEIRA AND GUIMARA

Section I

LUIZ FERNANDO REZENDE

Sirtuins and metabolic disease

3.1 Introduction 3.2 Tissue-specific sirtuin-modulated metabolic regulation 3.3 Nutrition as a therapeutic model for sirtuin regulation 3.4 Resveratrol 3.5 Gallic acid 3.6 Nonresveratrol related sirtuin activators 3.7 Food and sirtuins 3.8 Conclusion References

1. Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide KENNETH MAIESE

Abbreviations 1.1 Noncommunicable diseases 1.2 Metabolic disorders 1.3 Novel therapeutic strategies with sirtuins for metabolic disease 1.4 Silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) 1.5 SIRT1, metabolic function, and obesity 1.6 SIRT1 and AMP-activated protein kinase 1.7 SIRT1, mTOR, and metabolic disease 1.8 SIRT1, nicotinamide, and cellular metabolism 1.9 Future considerations Acknowledgments References

3 4 4 6

42 44 47 48 48 50 52 52

KULTIGIN TURKMEN

4.1 Introduction Part 1 4.2 Sirtuin 1 (SIRT1) in normal physiology Part 2 4.3 Diabetes mellitus and sirtuins 4.4 Hypertension and sirtuins 4.5 Novel treatment options in diabetes mellitus and diabetic kidney disease 4.6 Conclusion and future perspectives References

YI FANG AND XIAOLING LI

Introduction Stem cells and sirtuins SIRT1 in stem cell biology SIRT2 in stem cell biology SIRT3 in stem cell biology SIRT6 in stem cell biology SIRT7 in stem cell biology

39

4. Sirtuins in diabetes mellitus and diabetic kidney disease

6 7 8 9 10 11 13 13

2. Sirtuins in metabolic and epigenetic regulation of stem cells 2.1 2.2 2.3 2.4 2.5 2.6 2.7

34 35

25 26 26 31 32 32 33

61 62 62 65 65 71 71 72 73

5. Sirtuins and mitochondrial dysfunction JIAN-LI HE, TIAN-SHI WANG AND YI-PING WANG

5.1 Sirtuins are nutrient sensors 5.2 Sirtuins and mitochondrial biogenesis 5.3 Sirtuins and mitochondrial metabolism

vii

79 80 82

viii 5.4 Sirtuins and mitochondrial dysfunction in human diseases 5.5 Feasible clinical targets: posttranslational modifications of sirtuins regulate mitochondrial function Acknowledgments References

Contents

82 85 86 86

6. Sirtuins in immunometabolism HONGXIU YU

6.1 Brief introduction of immunometabolism 6.2 Role of sirtuins in immunometabolism 6.3 Conclusion and future considerations References

91 93 97 98

7. Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation MAJA GRABACKA AND PRZEMYSLAW M. PLONKA

Abbreviations 7.1 Introduction—advantages of possessing mitochondria 7.2 Mitochondrial sirtuins 7.3 Lipoylation of multienzymatic complexes is essential for mitochondrial metabolism 7.4 Alternative lipoylation and its metabolic consequences 7.5 Regulation of pyruvate dehydrogenase complex by mitochondrial sirtuins 7.6 Alpha ketoglutarate dehydrogenase complex regulates gene expression 7.7 Fluctuations of the intracellular concentration of organic acids has far-reaching implications 7.8 Ketogenic enzymes ACAT1 and HMGCS2 as substrates for Sirt3 and Sirt5 7.9 Antagonistic roles of mitochondrial sirtuins in fed and fasted state 7.10 The interplay between Sirt3 and isocitrate dehydrogenase in cancer cells 7.11 Tumor-suppressing and tumor-promoting activities of sirtuins in the context of glutamine and glucose metabolism 7.12 Sirtuins regulate iron sulfur cluster assemblage 7.13 Mitochondrial fatty acid synthesis is linked to Fe S cluster assembly and protein lipoylation—implications for cancer cell metabolism 7.14 Consequences of Fe S cluster defects in cancer cells 7.15 Deoxyribonucleotide synthesis—toward the as yet unexplored areas of sirtuin research 7.16 Perspectives—evolutionary implications and new directions in cancer treatment References

104 105 106 106

Section II Sirtuins and cancer 8. Sirtuins and the hallmarks of cancer TALITA H.B. GOMIG, TAYANA S. JUCOSKI, ERIKA P. ZAMBALDE, ALEXANDRE L.K. AZEVEDO, DANIELA F. GRADIA AND ENILZE M.S.F. RIBEIRO

8.1 Introduction 8.2 Sirtuins in sustaining proliferative signaling and evading growth suppressors 8.3 Sirtuins and resisting cell death 8.4 Sirtuins in tumor-promoting inflammation and immune system function 8.5 Sirtuins in angiogenesis 8.6 Sirtuins in invasion and metastasis 8.7 Sirtuins in genome instability and replicative immortality 8.8 Sirtuins in reprogramming energy metabolism 8.9 Sirtuins and cancer therapy 8.10 Concluding remarks References

109

9. The bifunctional roles of sirtuins and their therapeutic potential in cancer

110

YEUAN TING LEE, YI JER TAN, PEI YI MOK, AYAPPA V. SUBRAMANIAM AND CHERN EIN OON

111 112 113

9.1 The mammalian sirtuins 9.2 Sirtuin modulators 9.3 Conclusion and future perspectives Acknowledgment References

129 132 135 136 137 137 138 139 141 142 142

153 160 168 169 169

114 115 115 116

116 118 119 120 121

10. Sirtuins and next generation hallmarks of cancer: cellular energetics and tumor promoting inflammation ROBERT KLESZCZ AND WANDA BAER-DUBOWSKA

10.1 Introduction: an overview of sirtuins involvement in inflammation and cancer metabolism 10.2 Nuclear and cytosolic sirtuins involvement in metabolism of cancer and inflammatory cells 10.3 Mitochondrial sirtuins 10.4 Sirtuins indeed link metabolism, inflammation, and cancer? 10.5 Conclusions and perspectives References

179 180 184 188 190 190

Contents

11. Sirtuins and cellular metabolism in cancers

13. Sirtuin signaling in hematologic malignancies

ZHEN DONG AND HONGJUAN CUI

RYAN A. DENU

11.1 The metabolic characteristics of cancers 11.2 The regulatory modes of sirtuins in controlling cellular metabolism 11.3 Direct epigenetic control of cellular metabolism by sirtuins 11.4 Direct posttranslational control of cellular metabolism by sirtuins 11.5 Indirect control of cellular metabolism by sirtuins 11.6 Conclusions References

195 197 198 200 206 211 211

12. Dual role of sirtuins in cancer

233 234 235 244 248 249 250

14. Impacts of sirtuin1 and sirtuin3 on oral carcinogenesis SHAJEDUL ISLAM, YOSHIHIRO ABIKO, OSAMU UEHARA, YASUHIRO KURAMITSU AND ITSUO CHIBA

MARGALIDA TORRENS-MAS AND PILAR ROCA

12.1 Introduction 12.2 Sirtuins and cancer metabolism 12.3 Sirtuins and oxidative damage 12.4 Sirtuins, genomic stability, and DNA repair 12.5 Sirtuins and metastasis 12.6 Sirtuins and cancer stem cells 12.7 Sirtuins and chemoresistance 12.8 Sirtuins: tumor suppressors or promoters? References

Abbreviations 13.1 Introduction 13.2 Hematologic malignancies 13.3 Sirtuins regulate pathways important for hematologic malignancies 13.4 Therapeutic opportunities 13.5 Conclusions References

ix

219 219 221 221 222 223 223 224 226

14.1 14.2 14.3 14.4

Introduction Overview of sirtuins Involvement of sirtuins in oral cancer Potential therapeutic implications of sirtuins in oral cancer 14.5 Concluding remarks References

Index

259 260 264 269 271 271

275

List of contributors

Yoshihiro Abiko Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan

Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China Shajedul Islam Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan; Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan

Alexandre L.K. Azevedo Genetics Postgraduation Program, Genetics Department, Federal University of Parana´, Curitiba, Brazil Wanda Baer-Dubowska Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, ´ Poland Poznan,

Tayana S. Jucoski Genetics Postgraduation Program, Genetics Department, Federal University of Parana´, Curitiba, Brazil

Itsuo Chiba Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan

Robert Kleszcz Department of Pharmaceutical Biochemistry, ´ Poland Poznan University of Medical Sciences, Poznan, Yasuhiro Kuramitsu Advanced Research Promotion Centre, Health Sciences University of Hokkaido, Hokkaido, Japan

Hongjuan Cui State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture and Textile and Biomass Science, Southwest University, Chongqing, P. R. China; Cancer Center, Medical Research Institute, Southwest University, Chongqing, P. R. China Ryan A. Denu University of Wisconsin-Madison, Madison, WI, United States

Yeuan Ting Lee Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia Xiaoling Li Signal Transduction Laboratory, Institute of Environmental Health Sciences, Triangle Park, NC, United States

National Research

Kenneth Maiese Biotechnology and Venture Capital Development, Office of Translational Alliances and Coordination, National Heart, Lung, and Blood Institute; Cellular and Molecular Signaling, New York, NY, United States

Zhen Dong State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture and Textile and Biomass Science, Southwest University, Chongqing, P. R. China; Cancer Center, Medical Research Institute, Southwest University, Chongqing, P. R. China

Pei Yi Mok Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia

Yi Fang Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States

Janaina Ribeiro Oliveira Laboratory of Health Science, Postgraduate Program in Health Sciences; State University of Montes Claros (UNIMONTES), Montes Claros, Brazil

Talita H.B. Gomig Genetics Postgraduation Program, Genetics Department, Federal University of Parana´, Curitiba, Brazil

Chern Ein Oon Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia Przemyslaw M. Plonka The Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, The Jagiellonian University in Krako´w, Krako´w, Poland

Maja Grabacka The Department of Biotechnology and General Technology of Foods, Faculty of Food Technology, University of Agriculture in Krako´w, Krako´w, Poland

Luiz Fernando Rezende Laboratory of Health Science, Postgraduate Program in Health Sciences; State University of Montes Claros (UNIMONTES), Montes Claros, Brazil

Daniela F. Gradia Genetics Postgraduation Program, Genetics Department, Federal University of Parana´, Curitiba, Brazil

Enilze M.S.F. Ribeiro Genetics Postgraduation Program, Genetics Department, Federal University of Parana´, Curitiba, Brazil

Victor Hugo Dantas Guimara˜es Laboratory of Health Science, Postgraduate Program in Health Sciences; State University of Montes Claros (UNIMONTES), Montes Claros, Brazil

Pilar Roca Translational Oncology Multidisciplinary Group, Research Institute of Health Sciences (IUNICS), University of Balearic Islands, Health Research Institute of the Balearic Islands (IdISBa), E-07122 Balearic Islands, Palma, Spain; Ciber Obesity and Nutrition Physiopathology (CIBEROBN, CB06/03), Health Institute Carlos III, Madrid, Spain

Jian-Li He Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China; State Key Laboratory of Oncogenes and Related Genes, Renji

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List of contributors

Se´rgio Henrique Sousa Santos Postgraduate Program in Food and Health; Food Engineering School, Agricultural Sciences Institute (ICA), Federal University of Minas Gerais (UFMG), Montes Claros, Brazil; Laboratory of Health Science, Postgraduate Program in Health Sciences; State University of Montes Claros (UNIMONTES), Montes Claros, Brazil Ayappa V. Subramaniam Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia Yi Jer Tan Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia Margalida Torrens-Mas Translational Oncology Multidisciplinary Group, Research Institute of Health Sciences (IUNICS), University of Balearic Islands, Health Research Institute of the Balearic Islands (IdISBa), E-07122 Balearic Islands, Palma, Spain Kultigin Turkmen Division of Nephrology, Department of Internal Medicine, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey Osamu Uehara Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and

Development, School of Dentistry, Health University of Hokkaido, Hokkaido, Japan

Sciences

Tian-Shi Wang Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China Yi-Ping Wang Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, P. R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China Hongxiu Yu Institutes of Biomedical University, Shanghai, P. R. China

Sciences,

Fudan

Erika P. Zambalde Genetics Postgraduation Program, Genetics Department, Federal University of Parana´, Curitiba, Brazil

About the editor

Kenneth Maiese is an internationally recognized physician-scientist, healthcare executive, and editor with broad research, clinical, and leadership experience in academia, the federal government, and industry. He was born and raised in New Jersey and was the Valedictorian of his high school class at Pennsauken High School. He graduated from the University of Pennsylvania Summa cum Laude with Distinction and was a Teagle Scholar, Grupe Scholar, and Joseph Collins Scholar at Weill Medical College of Cornell University. Dr. Maiese was subsequently trained as a physician-scientist at Cornell, the National Institutes of Health, and as a senior executive at the Harvard T.H. Chan School of Public Health. He has extensive experience in academic medicine, healthcare delivery, business development, managed care, biotechnology, and drug development, holding positions as member and advisor for the National Institutes of Health Biotechnology and Venture Capital Development, National Institutes of Health Innovation Network, Chief Medical Officer, tenured Professor and Chair and Chief of Service of the Department of Neurology and Neurosciences of Rutgers University, Global Head of Translational Medicine and External Innovation, Board Member of the Cancer Institute of New Jersey, Steering Committee Member for the Foundation for the National Institutes of Health, tenured Professor in Neurology, Anatomy & Cell Biology, Molecular Medicine, the Barbara Ann Karmanos Cancer Institute, and the National Institute of Health Center at Wayne State University. He is the Founding Editor and Editor-in-Chief of multiple highly successful international journals. Dr. Maiese maintains therapeutic and scientific expertise in multiple medical disciplines, regulatory policy, and drug commercialization. His work has to elucidate a number of new avenues for the fruitful discovery of innovative strategies to treat neurodegenerative diseases, cardiovascular disorders, metabolic dysfunction, and cancer and he has led the development of first-in-class pharmaceuticals. Early in his career, Dr. Maiese received outstanding investigator awards, received the Hoechst Award for exceptional basic science work, was named a Johnson & Johnson Distinguished Investigator, was chosen as a Henrietta B. and Frederick H. Bugher Foundation Investigator, received the Albrecht Fleckenstein Memorial Award for Distinguished Achievement in Basic Research, was elected to America’s Top Physicians and The Best of US Physicians, was recipient of Albert Nelson Marquis Lifetime Achievement Award, and was elected as an America’s Health Insurance Plans (AHIP) Executive Leadership Fellow. His highly cited work has received the distinction of “High Impact Research and Potential Public Health Benefit” by the National Institutes of Health. He has been fortunate to have benefited from continuous funding from sources that include the American Diabetes Association, the American Heart Association, the Bugher Foundation, the Johnson & Johnson Focused Giving Award, and the National Institutes of Health. His service on Executive Councils for Graduate Schools has fostered innovative graduate student training programs and he was elected as board and advisor member to develop and execute inaugural MD/PhD Degree Programs and new Translational Medicine Programs. He chairs national grant committees, formulates regulatory and utilization management policies for national clinical care guidelines, and is a chartered panel member or consultant for numerous national and international foundations as well as multiple study sections and special emphasis panels for the National Institutes of Health. Dr. Maiese is frequently honored as the chairperson and/or the plenary and keynote speaker for a number of international symposiums, organizations, and presentations to federal policy makers.

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Preface

believed that at least another 400 million individuals either suffer from metabolic disease or are at risk for developing DM. These estimates for the number of individuals who may be undiagnosed or at risk to develop DM are expected to increase to 700 million by the year 2045. Furthermore, at least 7 million individuals over the age of 18 remain undiagnosed with DM. Prevalence of DM also has increased from 9.5% during the period of 1999 2002 to 12% during the period of 2013 16. Risk factors for developing complications of DM include tobacco consumption, lack of physical activity, hypertension, and elevated serum cholesterol. Obesity is considered to be an additional risk factor for the development of DM. Obesity and excess body fat can increase the risk of developing DM and can affect stem cell proliferation, agingrelated illnesses, inflammation, oxidative stress injury, and mitochondrial function. In regards to financial impact, the cost for the care of patients with DM is estimated to be at least US$ 760 billion, and these costs consume more than 17% of the Gross Domestic Product in the United States. Loss of function and disability as a result of DM leads to another estimated US$ 69 billion. Interestingly, cancer and DM share not only common risk factors but also biological mechanisms that may influence each of these diseases. Cancer and DM share the risk factors of obesity, poor nutrition, aging, and inactivity. The mechanisms that link cancer and DM may involve hyperglycemia, hyperinsulinemia, and inflammation. As a result, promotion of proper nutrition, exercise, and weight management can improve outcomes for individuals with cancer or DM. DM, primarily type 2, is associated with increased risk for the development of cancer in the liver, pancreas, colon, rectum, breast, bladder, and endometrial. Individuals with DM also have an increased risk for the development of non-Hodgkin’s lymphoma. In general, with some exceptions, women with DM are approximately 27% more likely to develop cancer when compared to women without DM, and men with DM are 19% more likely to develop cancer when compared to men without DM. In addition, some therapies for DM, such as metformin, may be associated with a lower risk for the development of cancer.

Life expectancy continues to increase throughout the world and is approaching 80 years of age for individuals. The rise in life span across the globe also has paralleled the increase observed with noncommunicable diseases (NCDs). NCDs are increasing in incidence throughout the world. At least 70% of deaths that are documented each year are the result of NCDs. Interestingly, NCDs affect a significant proportion of the population in low- and middle-income countries with at least one-third of the population under the age of 60 suffering from NCDs. Of the greater than 40 million individuals that die each year from NCDs, at least 15 million individuals are between 30 and 69 years old. The 10 leading causes of death in the world are cardiac disease, cancer, trauma, respiratory disease, stroke, Alzheimer’s disease, diabetes mellitus (DM), influenza and pneumonia, kidney disease, and suicide. Of these NCDs, cancer is a significant concern since it is the second leading cause of death throughout the world. It is estimated that approximately one in six deaths result from cancer, and at least 70% of cancer deaths are in low- and middle-income countries. The most significant risk factor for cancer is tobacco use which represents more than 20% of cancer deaths. High body mass index, lack of physical activity, low fruit and vegetable intake, alcohol consumption, and tobacco use together lead to greater than 33% of cancer-associated deaths. Furthermore, cancer also has a significant effect on world economies and creates a large financial drain on resources. It is estimated that only 20% 30% of low- and middle-income countries have the appropriate capability to treat cancer-related illnesses. In contrast, over 90% of high-income countries have effective treatment services for cancer. Recent estimates report that in the United States, the cost for cancer therapy is almost US$ 150 billion, and the estimated lost earnings for individuals in the United States as a result of cancer-related illnesses exceed another US$ 100 billion per year. In addition to cancer, metabolic disorders that include DM also represent a significant component of NCDs. At present, at least 500 million individuals have DM and approximately 80% of adults with DM are living in low- and middle-income countries. It is

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Current treatments for both cancer and DM remain limited and, in many cases, cannot block disease progression. For example, early diagnosis and rapid treatment of DM can provide some degree of protection and may partially limit the progression of DM. Yet, even under the best of circumstances, tight serum glucose control does not blunt the complications that can arise during DM or completely prevent the risk of tumorigenesis. As a result, novel avenues for therapeutic strategies to address cancer and metabolic disorders are extremely warranted. An exciting prospect for the development of innovative therapeutics involves sirtuins. Sirtuins are histone deacetylases that have an intricate role in the onset and development of cancer and metabolic disease. Sirtuins are expressed throughout the body, have wideranging biological effects, and significantly affect both cellular survival and longevity during acute and longterm illnesses. In general, sirtuins have an intricate and complex role in the pathology, progression, and treatment of multiple disease entities that involve cancer, metabolic disease and DM, neurodegenerative disorders, cognitive loss, behavior disorders, cardiovascular disease, atherosclerosis, immune system dysfunction, reproductive disease, endocrine disorders, gastrointestinal disease, and aging-related disorders. In particular, sirtuins can oversee critical pathways that involve stem cell maintenance, cellular proliferation, metabolic homeostasis, apoptosis, and autophagy that can impact cellular dysfunction and unchecked cellular growth that can occur during cancer and metabolic disease. Sirtuin Biology in Cancer and Metabolic Disease: Cellular Pathways for Clinical Discovery is a unique resource for detailing the basic and clinical roles of sirtuins, recent discoveries on the understanding of sirtuin biology, and the broad applicability for sirtuin pathways to be targeted for the clinical care of cancer and metabolic disorders. With chapters authored by internationally recognized experts, this book fills a significant void to provide a foundation for elucidating the intimate relationship between cancer and metabolic disease that intersects with sirtuin pathways. Each chapter offers an intuitive perspective of advances on the application of sirtuin pathways for cancer and

metabolic disease that will be become a “go-to” resource for a broad audience of scientists, physicians, pharmaceutical industry experts, nutritionists, and students. Sirtuin Biology in Cancer and Metabolic Disease: Cellular Pathways for Clinical Discovery begins with Section I, Sirtuins and Metabolic Disease. In this section, the role of sirtuins in metabolic disease, relation to other integral biologic pathways of sirtuins, regulation of stem cells, supplementation of nutritional requirements, immune function modulation, and maintenance of mitochondrial function are presented. Additionally, a discussion is expanded on sirtuin pathways that affect glucose sensitivity and tolerance, obesity, the nervous system, renal disease, and the link between energy metabolism and transformation into cancer. Section II, Sirtuins and Cancer, provides a critical perspective for the role of sirtuins as an agent that oversees tumorigenesis and metabolic pathways that influence cancer cells. Sirtuins are discussed as both tumor-promoting and suppressor agents that can change depending upon environmental stimuli: signal transduction pathways of sirtuins are highlighted that involve inflammatory modulation, invasion and migration capabilities of sirtuins are dissected, the impact of changing cellular metabolism dynamics is highlighted, and the development of sirtuin modulators as chemotherapeutic agents is presented. In addition, the role of sirtuins is examined for multiple cancer cell growths, such as oral carcinogenesis and hematologic malignancies, and the sirtuin mechanisms that lead to cellular inflammation and the development of metastatic disease are presented. Sirtuin Biology in Cancer and Metabolic Disease: Cellular Pathways for Clinical Discovery offers a compelling and thought-provoking perspective of the examination of the intriguing biology of sirtuins that ties cancer and metabolic disease together and provides a critical platform for the development of sirtuin-based novel therapeutic strategies to effectively treat cancer and metabolic disorders with precision in order to minimize any potentially detrimental clinical outcomes. Kenneth Maiese Editor

Acknowledgment

My sincere appreciation goes to the extraordinary devotion and expertise of our contributors. The ongoing support, time, and undertakings that I have received from the Elsevier team, especially, Tari Broderick and Timothy Bennett, have made this book a reality.

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C H A P T E R

1 Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide Kenneth Maiese1,2 1

Biotechnology and Venture Capital Development, Office of Translational Alliances and Coordination, National Heart, Lung, and Blood Institute; 2Cellular and Molecular Signaling, New York, NY, United States O U T L I N E Abbreviations

3

1.6 SIRT1 and AMP-activated protein kinase

8

1.1 Noncommunicable diseases

4

1.7 SIRT1, mTOR, and metabolic disease

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1.2 Metabolic disorders

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1.8 SIRT1, nicotinamide, and cellular metabolism

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1.3 Novel therapeutic strategies with sirtuins for metabolic disease

1.9 Future considerations

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6

Acknowledgments

13

1.4 Silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae)

6

References

13

1.5 SIRT1, metabolic function, and obesity

7

Abbreviations AGEs AgRP AD AMPK Aβ Bad Deptor DNA DM EPO 4EBP1 FRAP SGK1 HbA1c IGF-1 IRS-1 FoxOs mLST8

advanced glycation end products agouti-related peptide Alzheimer’s disease AMP-activated protein kinase β-amyloid BCL2-associated agonist of cell death DEP domain-containing mTOR interacting protein deoxyribonucleic acid diabetes mellitus erythropoietin eukaryotic initiation factor 4E (eIF4E)-binding protein 1 FKBP12-rapamycin-associated protein glucocorticoid induced protein kinase 1 hemoglobin A1c insulin growth factor-1 insulin receptor substrate 1 mammalian forkhead transcription factors mammalian lethal with Sec13 protein 8, termed mLST8

Sirtuin Biology in Cancer and Metabolic Disease. DOI: https://doi.org/10.1016/B978-0-12-822467-0.00006-1

3

© 2021 Elsevier Inc. All rights reserved.

4 mSIN1 mTOR mRNA mTORC1 mTORC2 NAD1 NADP1 NMN NCDs NF-κB p70S6K PPAR PGC PS PDK1 PI 3-K PRAS40 POMC Akt AGC PKCα PTP LKB1 SIRT1 TNF-α UCP

1. Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

mammalian stress-activated protein kinase interacting protein mechanistic target of rapamycin messenger ribonucleic acid mTOR Complex 1 mTOR Complex 2 nicotinamide adenine dinucleotide nicotinamide adenine dinucleotide phosphate nicotinamide mononucleotide noncommunicable diseases nuclear factor-κB p70 ribosomal S6 kinase peroxisome proliferator-activated receptor peroxisome proliferator-activated receptor gamma coactivator phosphatidylserine phosphoinositide-dependent kinase 1 phosphotidylinositide 3-kinase proline rich Akt substrate 40 kDa proopiomelanocortin protein kinase B protein kinase A/protein kinase G/protein kinase C protein kinase C-α protein tyrosine phosphatase serine-threonine liver kinase B1 silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) tumor necrosis factor-α uncoupling protein

1.1 Noncommunicable diseases Metabolic disorders, that include diabetes mellitus (DM), are considered to be a leading cause of death in the world as part of noncommunicable diseases (NCDs) [15]. NCDs are increasing in incidence throughout the world [2,68] and according to the World Health Organization, almost 70% of deaths that are documented each year are the result of NCDs [9,10]. Both wealthy and low-income countries are affected by NCDs. Greater than 10% of the population less than 60 years of age is affected in high-income countries [9]. NCDs affect a greater proportion of the population in low- and middle-income countries with at least one-third of the population under the age of 60 suffering from NCDs. Of the over 40 million individuals that die each year from NCDs, 15 million individuals are younger, with ages between 30 and 69 years old. The rise in NCDs follows an observed increase in life expectancy of the world’s population [11,12]. After a recent reduction that has been reported in deaths from opioid overdoses, life expectancy is increasing again in the United States [13]. The age of the world’s population continues to increase with new estimates of life expectancy approaching 80 years of age [14]. With life expectancy marked by a 1% decrease in the age-adjusted death rate from the years 2000 through 2011 [15], the number of individuals over the age of 65 has been observed to double during the prior 50 years [16]. In consideration of less developed nations, the number of older individuals in large developing countries such as India and China also will increase from 5% to 10% over the next several decades [17,18]. Although many factors may account for the observed increased in life span for the world’s population, the 10 leading causes of death, which are cardiac disease, cancer, trauma, respiratory disease, stroke, Alzheimer’s disease (AD), DM, influenza and pneumonia, kidney disease, and suicide, have remained the same [13]. Yet improvements in preventive medical care, more focused public health guidelines and sanitation measures, and new treatments for multiple disorders that involve endocrine disease, metabolic disorders, and nutrition have assisted with improvements in life span longevity [3,1926].

1.2 Metabolic disorders As a significant component of NCDs, DM is a disorder that is increasingly being targeted for the development of new treatment strategies to reduce death and disability for the world’s population [2729] (Table 1.1). Approximately 80% of adults with DM are living in low- and middle-income countries [4]. Currently, almost

I. Sirtuins and metabolic disease

1.2 Metabolic disorders

5

TABLE 1.1 B-cell function (Mitochondrial D). Innovative treatment strategies with SIRT1 for metabolic disease • Metabolic disorders, such as diabetes mellitus (DM), are a significant component of the increased prevalence of noncommunicable diseases (NCDs) and affect all organs and systems of the body. • Given the challenges with limited therapeutic options for metabolic disease, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and the pathways with AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), and nicotinamide offer exciting avenues for innovative treatment strategies for metabolic disease. • SIRT1 can increase life span in higher organisms and limit oxidative stress injury, block β-amyloid (Aβ) and tau toxicity that can affect cognition, prevent apoptotic cell death, limit the development of obesity, regulate nutritional intake, maintain mitochondrial function, and oversee insulin sensitivity. • AMPK through autophagy activation can reduce insulin resistance, improve cognition in models of Alzheimer’s disease and DM, promote clearance of Aβ and tau, preserve β-cell function, and block hyperglycemic cell death. • mTOR can improve insulin secretion, decrease insulin resistance, limit apoptotic cell death, foster the differentiation of adipocytes, block Aβ toxicity, and maintain mitochondrial function and neurovascular cell survival independently and through the trophic factor erythropoietin (EPO). • Nicotinamide, a product and inhibitor of SIRT1, can decrease insulin resistance, prevent muscle atrophy during DM, reduce mitochondrial stress through AMPK, reduce hemoglobin A1c (HbA1c) levels, and prevent palmitate-induced hepatotoxicity via SIRT1-dependent induction of autophagy. • SIRT1 has an intimate but complex relationship with mTOR, AMPK, and nicotinamide such that biological feedback pathways exist that require a fine balance in modulation in order to achieve optimal clinical efficacy.

500 million individuals have DM [5,17,3032]. At least another 400 million individuals are believed to either suffer from metabolic disease or be at risk for developing DM [4,3335]. In addition, according to the International Diabetes Federation the number of individuals with DM is expected to rise to 700 million individuals by the year 2045 [4]. In the United States, almost 35 million individuals, which represents approximately 10% of the population, are diagnosed with DM [1]. At least seven million individuals over the age of 18 remain undiagnosed with DM and in the year 2018 it was estimated that almost 35% of adults in the United States had prediabetes based on their fasting glucose and hemoglobin A1c (HbA1c) levels [36]. Prevalence of DM also has increased from 9.5% during the period of 19992002 to 12% during the period of 201316. In the adult population, it was noted that prevalence varied by indicators of socioeconomic status, such as education level. At least 13% of adults with less than a high school education had DM compared to almost 10% of individuals with a high school education and DM and 7.5% of individuals with greater than a high school education and DM. Risk factors for developing complications of DM included tobacco consumption, physical inactivity, hypertension, and elevated serum cholesterol [2]. Obesity is considered to be another risk factor for the development of DM. Obesity results in impaired glucose tolerance that leads to DM progression [24,3743]. Obesity and excess body fat can increase the risk of developing DM in young individuals [44] and can affect stem cell proliferation, aging, inflammation, oxidative stress injury, and mitochondrial function [39,4551]. In regard to the financial considerations for DM, at least US$ 20,000 are required to care for each individual with DM per year. The care for patients with DM equals approximately US$ 760 billion [4]. This care consumes more than 17% of the Gross Domestic Product in the United States, per the Centers for Medicare and Medicaid Services (CMS) [52]. When considering the loss of function and disability that result from DM individuals, an estimated US$ 69 billion are consumed from reduced productivity linked to DM. The toxic effects of DM do not exclude any organs of the body and can affect all cellular systems [53]. In the peripheral nervous system, at least 70% of individuals with DM can develop diabetic peripheral neuropathy. DM can result in autonomic neuropathy [54] and peripheral nerve disease [5558]. Assessments of peripheral neuropathies can be challenging, since the disorder is chronic in nature, may be subclinical, and prior deficits may go undetected even after improved control over glucose homeostasis has been initiated. In the central nervous system, DM can cause insulin resistance and dementia in patients with AD [2,6,11,29,53,5961]. DM can affect multiple cellular pathways that lead to the progression of cognitive loss [17,6267]. DM also has been tied to mental illness [68,69], cerebral vascular injury [17,34,7073], impairment of microglial activity [29,5961], and can impact stem cell proliferation [17,41,6266]. DM also can result in endothelial dysfunction [11,17,7476], cardiovascular disease [35,37,75,7783], retinal disease [8486], and immune and infectious disorders [8793].

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1. Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

1.3 Novel therapeutic strategies with sirtuins for metabolic disease Given the growing prevalence of DM, the significant number of individuals that remain undiagnosed with DM, and the severe financial impact on global economies, new and innovative therapeutic strategies are vital to be developed for the treatment of metabolic disorders, such as DM. With conventional therapies, early diagnosis of DM and rapid treatment can offer some degree of protection and may inhibit the progression of DM [5,11,9498]. However, even under the best of circumstances, tight serum glucose control does not blunt the complications that can arise during DM [2,99]. Careful nutritional and exercise management also is considered to be important for DM care, but in some cases these strategies may be less than beneficial dependent upon the degree of reduced oral intake and a decrease in organ mass through processes that involve autophagy [100]. DM also has additional risk factors when one considers the development of neurodegenerative disorders and cognitive loss that can be compounded by hypertension, low education in early life, and tobacco use [2,29,53,101]. For example, vascular disease as a result of DM may lead to dementia [2,6,8,11,53,102104]. As a result, new avenues for therapeutic strategies to address metabolic disorders are urgently needed. One innovative strategy that offers exciting prospects involves the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and its associated pathways with AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), and the vitamin nicotinamide (Table 1.1).

1.4 Silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) SIRT1 is a member of the sirtuin family (sirtuin 1) and a histone deacetylase [11,17,22,105114] that can transfer acetyl groups from ε-N-acetyl lysine amino acids to the histones of deoxyribonucleic acid (DNA) to control transcription (Table 1.1). Seven mammalian homologues of Sir2 that include SIRT1 through SIRT7 have been identified. These histone deacetylases can control cellular metabolism, cell senescence, cell function, cell injury, and posttranslation modifications of proteins [2,8,115118]. SIRT1 depends upon the substrate nicotinamide adenine dinucleotide (NAD1) [90,109,119121]. Histone deacetylases are enzymes that transfer acetyl groups from ε-N-acetyl lysine amino acids that exist on the histones of DNA to regulate transcription. Although histone deacetylases primarily oversee DNA transcription, they may be involved with posttranslational changes of proteins as well such as the ability of SIRT1 to control the posttranslational phosphorylation of mammalian forkhead transcription factors [122,123]. During deacetylase reactions, sirtuins, that include SIRT1, transfer the acetyl residue from the acetyllysine residue of histones to the ADP-ribose moiety of NAD1, resulting in the production of nicotinamide, 20 -O-acetyl ADP ribose, and deacetylated proteins. SIRT1 expression is present in the brain, heart, liver, pancreas, skeletal muscle, spleen, and adipose tissues. In the cell, SIRT1 is present in the nucleus and cytoplasm with dominant expression in the nucleus [11,85,90,106,112,118,124126]. In disorders that can lead to oxidative stress, such as DM [5,11,44,94,98,127,128], SIRT1 activation can decrease oxidative stress, prevent diabetic retinal injury, and block cell injury that would lead to memory loss [2,85,112,129135]. Activation of SIRT1 has been associated with reduction in oxidative stress and the protection of cognition [136,137]. Oxidative stress may lead to aberrant cell cycle reentry that can lead to neuronal death during AD [138,139]. Limiting the generation of reactive oxygen species in models of AD has led to reduced toxicity of Aβ, suggesting that oxidative stress is a critical component in the pathology of AD [126]. SIRT1 may directly block Aβ and tau toxicity and preserve mitochondrial function. SIRT1 may limit the toxicity of Aβ [140143]. SIRT1 also can oversee neurovascular protection in the brain that would be relevant for ischemicmediated dementia that can occur during DM [17,89,90,105,112,119,120,130,144147]. SIRT1 can increase life span in higher organisms and protect against oxidative stress in neuronal cells [129]. Pancreatic SIRT1 activation through exercise also has been shown to potentially reduce oxidative stress complications during diabetes [148]. SIRT1 can control pathways of apoptosis and autophagy [113,114] (Table 1.1). In regard to autophagy, activation of autophagy in human lung cancer cells leads to increased cell survival. SIRT1 inhibition leads to prosurvival autophagy activity and inhibition of apoptosis in these cells [149]. SIRT1 also can upregulate autophagy and mitochondria function in embryonic stem cells during periods of oxidative stress [150]. Through SIRT1 activity and autophagic flux, senescence is inhibited in vascular endothelial cells [151]. SIRT1 is also tied to apoptosis. SIRT1 activation blocks external membrane phosphatidylserine (PS) exposure during the early phases of apoptosis in mature cells [123,152154]. SIRT1 can limit apoptosis initiated by tumor necrosis factor-α (TNF-α) in endothelial progenitor cells [155]. Loss of SIRT1 expression in endothelial progenitor

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1.5 SIRT1, metabolic function, and obesity

7

cells leads to apoptotic cell death that can occur in smokers and chronic obstructive disease patients [156]. Apoptotic cell death during oxidative stress in cardiac cells is minimized through the activation of SIRT1 [157].

1.5 SIRT1, metabolic function, and obesity SIRT1 plays a critical role in cellular metabolism [28,43,106,119,158,159] (Table 1.1). For example, SIRT1 can oversee the development of fat progression and obesity. SIRT1 in association with peroxisome proliferatoractivated receptor-γ (PPAR-γ) can control adipogenesis. SIRT1 protein can repress PPAR-γ to result in the mobilization of fatty acids from white adipocytes upon fasting and lead to the loss of fat through lipolysis [160]. PPAR-γ also can interact with SIRT1 and form a negative feedback to regulate SIRT1 expression and activity [161]. SIRT1 expression has been found to be depressed in adipose tissue in obese rodents. Loss of SIRT1 in white adipose cells results in the impairment of fatty acid mobilization. Treatment with resveratrol, an activator of SIRT1, can lead to calorie restriction to prevent obesity as a result of a high calorie diet in mice [162]. SIRT1 also has been shown to be expressed in anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus and regulate food intake and cellular metabolism [163]. Overexpression of SIRT1 in the hypothalamus prevents mammalian forkhead transcription factor 1 (FoxO1), a mammalian forkhead transcription family member [8,110,164], from promoting hyperphagia and weight gain [163]. Yet lack of SIRT1 in POMC neurons leads to obesity due to reduced energy expenditure [165]. Additional studies have shown that melatonin can reduce inflammation in adipocytes that can limit obesity through pathways that involve SIRT1 [48] and that decreased expression of SIRT1 during hyperglycemia and obesity can increase stroke infarct size [72]. In relation to cellular metabolic regulation, SIRT1 regulates the activity of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) through deacetylation. PGC-1α is a member of a family of transcriptional coactivators that includes PGC-1α, PGC-1β, and PGC-1 related coactivator (PRC). PGC-1α leads to gene transcription and increases the expression of genes that regulate mitochondrial functions and fatty acid oxidation [166]. Increased PGC-1α activity can function to protect against some metabolic diseases and improve mitochondrial biogenesis. SIRT1 can oversee PGC-1α activity in the liver to lead to gluconeogenic genes and hepatic glucose output. SIRT1 can control the ability of PGC-1α to repress glycolytic genes in response to fasting and pyruvate [167]. Hepatic SIRT1 with PPAR-α, a receptor that can increase free fatty acid uptake and decrease lipolysis, activates PGC-1α to lead to lipid homeostasis. SIRT1 deletion in the liver results in the loss of PGC-1α activity and the subsequent impairment of fatty acid oxidation, leading to the develop of hepatic steatosis during high-fat diets [168]. SIRT1 has an important role in the management of insulin sensitivity. During high-fat diets, increased SIRT1 activity can regulate glucose and hepatic lipid homeostasis and protects against metabolic syndrome [169]. SIRT1 activation also limits diabetic myocardial injury by inhibiting high mobility group box 1/nuclear factor-κB (NF-κB) pathway-associated proteins [170]. During the administration of high-fat diets, SIRT1 expression is decreased in the pancreas and liver and may be associated with insulin resistance [171]. SIRT1 has been shown to be markedly decreased in insulin-resistant cells and reduction of SIRT1 levels in gastrocnemius muscle leads to insulin resistance [172]. In addition, knockdown or blockade of SIRT1 activity impairs insulin signaling by interfering with insulin-stimulated insulin receptor phosphorylation and glycogen synthase [172]. On the other hand, overexpression of SIRT1 in the liver can attenuate hepatic steatosis and lead to improved glucose homeostasis [173]. Insulin sensitivity is improved in diabetic rats during exercise training through the activation of SIRT1 [148]. The ability of SIRT1 to improve insulin sensitivity may occur through a number of mechanisms that include modulation of fat mobilization [160], control of gluconeogenesis [167], and limiting the onset of inflammation [168]. SIRT1 also serves as a positive modulator of insulin signaling in insulin-sensitive organs and activates the insulin downstream target protein kinase B (Akt) through phosphotidylinositide 3-kinase (PI 3-K) [174]. In addition, SIRT1 can stimulate glucose-dependent insulin secretion from pancreatic β cells by repressing the uncoupling protein (UCP) gene UCP2 [175]. Resveratrol, an activator of SIRT1, can promote glucose-stimulated insulin secretion in insolinoma INS-1E cells and human islets that is dependent on the activity of SIRT1 [176]. SIRT1 also oversees insulin sensitivity through protein tyrosine phosphatase (PTP). In the PTP family [177182], PTP1B has been identified to negatively regulate insulin signal transduction by targeting the insulin receptor. PTP1B deficiency or inhibition leads to improved insulin sensitivity and glycemic control. SIRT1 overexpression or SIRT1 activation can reduce both the PTP1B messenger ribonucleic acid (mRNA) and protein levels during insulin resistance for improved glucose homeostasis. An increase in PTP1B expression prevents

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1. Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

SIRT1-mediated glucose uptake and insulin receptor phosphorylation in response to insulin stimulation, illustrating that SIRT1 improves insulin sensitivity through the repression of PTP1B [172].

1.6 SIRT1 and AMP-activated protein kinase SIRT1 may regulate insulin sensitivity and metabolism through the phosphorylation of AMPK and protect against metabolic syndrome [43,53,112,183,184] (Table 1.1). Activation of AMPK through phosphorylation functions to promote insulin sensitivity, fatty acid oxidation, and mitochondrial biogenesis. This leads to the generation of ATP and reduction in oxidative stress [2,12]. AMPK has been shown to limit the disability and hyperalgesia from diabetic neuropathy in animal models [57]. Diets associated with fish oil consumption can result in increased AMPK activity and block endothelial progenitor cell dysfunction and ischemic injuries [78]. AMPK can reduce insulin resistance, since the loss of AMPK results in reduced tolerance to the development of insulin resistance [185]. During periods of dietary restriction that may increase life span [129], AMPK can be one of several pathways to shift to beneficial oxidative metabolism [186]. AMPK can reduce ischemic brain damage in diabetic animal models [187], improve memory retention in models of AD and DM [188], offer elimination of ß-amyloid (Aß) in the brain [189], facilitate tau clearance [190], modulate chronic inflammation in neurodegenerative disorders [22,184,191], and prevent Aß neurotoxicity [192]. The AMPK pathway is relevant with current treatments used for DM and SIRT1. Biguanides and metformin rely upon AMPK and autophagy to restore cellular function. Metformin blocks mTOR activity, promotes autophagy, and can function at times in an AMPK-independent manner [193]. Through metformin, AMPK can become activated, leading to autophagy induction, and protecting against diabetic apoptotic cardiac cell loss [194]. Metformin also has been shown to prevent lipid peroxidation in the brain and spinal cord and to decrease caspase activity during toxic insults [195]. These observations of metformin to offer protection during DM may be associated with the ability of autophagic pathways to limit oxidative stress under some circumstances [38,196]. AMPK can oversee metabolic pathways through both apoptosis and autophagy. During metabolic disease, autophagy can remove misfolded proteins and eliminate nonfunctioning mitochondria to maintain β-cell function and prevent the onset of DM [197]. Exercise in mice has been demonstrated to promote the induction of autophagy and regulate glucose homeostasis [198]. Autophagy can improve insulin sensitivity during the administration of high-fat diets in mice [185] and may offer protection to microglia during acute glucose fluctuations [61]. During periods of hyperglycemia, AMPK increases basal autophagy activity [110,199] and maintains endothelial cell survival [76,200]. AMPK can modulate apoptosis and autophagy during coronary artery disease [201], cholesterol efflux [202], endothelial dysfunction during hyperglycemia [76], and oxidative stress [159,203]. Antisenescence activity also can be promoted by AMPK activation and the increase of autophagic flux [151]. Activation of autophagy pathways is not always beneficial and may require careful modulation during metabolic disease [42,53,59,61,89,93,204]. Increased activity of autophagy can lead to the loss of cardiac and liver tissue in diabetic rats during attempts to achieve glycemic control through diet modification [100]. During elevated glucose exposure, advanced glycation end products (AGEs), agents that can result in DM complications, have been shown to lead to autophagy activation and vascular smooth muscle proliferation that can result in atherosclerosis [205], as well as cardiomyopathy [206]. During elevated glucose exposure, autophagy can impair endothelial progenitor cells, lead to mitochondrial oxidative stress [207], and prevent angiogenesis [208]. Chronic inflammatory conditions such as lichen planus also have been tied to mTOR inhibition and autophagy activation [209]. In regard to SIRT1, SIRT1 can control AMPK through the AMPK kinase, serine-threonine liver kinase B1 (LKB1). Overexpression of SIRT1 results in the deacetylation of LKB1, leading to its translocation from the nucleus to the cytoplasm, where LKB1 activates AMPK [210]. AMPK, in turn, can the lead to the activation of SIRT1. AMPK cannot directly activate SIRT1, but may enhance SIRT1 activity. However, AMPK-mediated impairment of muscle differentiation during glucose restriction and PGC-1α-mediated gene expression is dependent upon SIRT1. AMPK activation enhances SIRT1 activity either by increasing cellular NAD1/NADH ratio, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the PGC-1α, FoxO1, and FoxO3a [211], or by upregulating nicotinamide phosphoribosyltransferase (Nampt) during glucose restriction, leading to increased NAD1 and decreased nicotinamide, an inhibitor of SIRT1 [212]. The SIRT1 activator resveratrol also has been demonstrated to increase AMPK activity through SIRT1-dependent or -independent mechanisms [211,213]. Resveratrol increases AMPK phosphorylation to protect cells against elevated glucose concentration, improve insulin sensitivity, and stimulate glucose transport. SIRT1 and AMPK can function to prevent hyperglycemic cell death in endothelial cells [76] and maintain mitochondrial homeostasis [43]. Increased

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AMPK activation limits myocardial infarct size in both nondiabetic and diabetic rat hearts following ischemia/ reperfusion, which may be mediated through the inhibition of mitochondrial permeability transition pore opening in cardiomyocytes [214]. AMPK signaling has been shown to reverse hyperalgesia during diabetic neuropathy in animal models [57].

1.7 SIRT1, mTOR, and metabolic disease A significant pathway for SIRT1 to impact metabolic disease and cellular survival involves mTOR [5,28,43,115,151,215217] (Table 1.1). mTOR is a 289-kDa serine/threonine protein kinase that is encoded by the single gene FRAP1 [2,218220]. mTOR can be referred to by other terms such as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 [113,221]. The target of rapamycin (TOR) was first described in Saccharomyces cerevisiae with the genes TOR1 and TOR2 [221]. Through the use of rapamycin-resistant TOR mutants, TOR1 and TOR2 were found to encode the Tor1 and Tor2 isoforms in yeast [222]. Rapamycin is a macrolide antibiotic in Streptomyces hygroscopicus that blocks TOR and mTOR activity [34]. mTOR serves as the principal component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) [223225] (Table 1.1). mTORC1 is composed of Raptor, Deptor (DEP domain-containing mTOR interacting protein), the proline rich Akt substrate 40 kDa (PRAS40), and mammalian lethal with Sec13 protein 8, termed mLST8 (mLST8) [2,113]. Rapamycin inhibits the activity of mTORC1 by binding to immunophilin FK-506-binding protein 12 (FKBP12) that attaches to the FKBP12-rapamycin-binding domain (FRB) at the carboxy (C)-terminal of mTOR to interfere with the FRB domain of mTORC1 [113]. mTORC1 is more sensitive to inhibition by rapamycin than mTORC2, but chronic administration of rapamycin can inhibit mTORC2 activity as a result of the disruption of the assembly of mTORC2 [184,220]. mTORC1 binds to its constituents through the protein Ras homologue enriched in brain (Rheb) that phosphorylates the Raptor residue serine863 and other residues that include serine859, serine855, serine877, serine696, and threonine706 [226]. The inability to phosphorylate serine863 limits mTORC1 activity, as observed through the use of site-direct mutation of serine863 [227]. mTOR can control Raptor activity and this activity can be blocked by rapamycin [227]. Deptor, also an inhibitor of mTORC1, prevents mTORC1 activity by binding to the FAT (FKBP12-rapamycin-associated protein (FRAP), ataxia-telangiectasia (ATM), and the transactivation/transformation domain-associated protein) domain of mTOR. If the activity of Deptor is lessened, Akt, mTORC1, and mTORC2 activities are increased [228]. PRAS40 blocks mTORC1 activity by preventing the association of p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) with Raptor [2,113,229,230]. Akt also is important in this pathway since mTORC1 activity is increased once phosphorylation of PRAS40 occurs by Akt. This releases the binding of PRAS40 and Raptor to sequester PRAS40 in the cell cytoplasm with the docking protein 14-3-3 [231234]. In contrast to Deptor and PRAS40, mLST8 promotes the activity of mTOR. This requires the binding of p70S6K and 4EBP1 to Raptor [235]. mLST8 also has a number of other functions. It can oversee insulin signaling through the mammalian transcription factor FoxO3 [89,236], is necessary for Akt and protein kinase C-α (PKCα) phosphorylation, and is required for Rictor to associate with mTOR [236]. In contrast to mTORC1, mTORC2 is composed of Rictor, Deptor, the mammalian stress-activated protein kinase interacting protein (mSIN1), mLST8, and the protein observed with Rictor-1 (Protor-1) [2,8,113]. mTORC2 controls cytoskeleton remodeling through PKCα and cell migration through the Rac guanine nucleotide exchange factors P-Rex1 and P-Rex2 and through Rho signaling [237]. mTORC2 fosters activity of protein kinases that include glucocorticoid induced protein kinase 1 (SGK1), a member of the AGC family of protein kinases. Protor-1, a Rictor-binding subunit of mTORC2, leads to SGK1 activity [238,239]. mSin1 is vital for the assembly of mTORC2 and for mTORC2 to phosphorylate Akt [240]. Rictor and mSIN1 phosphorylate Akt at serine473 and promote threonine308 phosphorylation through phosphoinositide-dependent kinase 1 (PDK1) to be protective for cellular survival. mTOR is intimately tied to cellular metabolic function and disease [2,34,57,241244]. Activation of mTOR may limit cognitive loss that can be a result of DM [2,28,113,245247]. For example, mTOR activation can prevent microglial injury during oxidative stress and limit Aß toxicity in neurons [232,246,248,249]. In addition, mTOR activation can prevent diabetic neuropathy [58] and reduce ischemic stroke injury in conjunction with circadian clock genes [2,22,250252].

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Decreased activity of mTOR has been shown to increase mortality in murine models of DM [253]. During mTOR inhibition with rapamycin, reduced β-cell function, insulin resistance, and decreased insulin secretion can promote the progression of DM [254]. Proper translocation of glucose transporters to the plasma membrane in skeletal muscle are also affected during loss of mTOR activity [255]. mTOR activation has been found to be diminished and this loss of mTOR may possibly be responsible for insulin resistance and the increased risk of vascular thrombosis in patients with metabolic syndrome [256]. Activation of mTOR pathways that involve p70S6K and 4EBP1 can improve insulin secretion in pancreatic β-cells and increase resistance to β-cell streptozotocin toxicity and obesity in mice [257]. Loss of p70S6K activity leads to hypoinsulinemia and glucose intolerance with decreased pancreatic β-cell size [258]. mTOR activity can protect pancreatic β-cells against cholesterolinduced apoptosis [259], lead to enhanced neuronal cell survival in cell models of DM [260], and prevent glucolipotoxicity [261]. mTOR activity can allow for the differentiation of adipocytes [262], prevent endothelial cell dysfunction during hyperglycemia [76], and preserve glucose homeostasis [263]. mTOR provides protection as part of the Mediterranean diet to reduce obesity in the population. The diet may reduce Aβ toxicity in astrocytes through enhanced Akt activity by consumption of polyphenol of olives and olive oil that ultimately could prevent the onset or progression of AD [242]. In addition, growth factors that offer cellular protection against oxidative stress, such as insulin-like growth factor-1 (IGF-1) [264267] and erythropoietin (EPO) [2,38,84,97,128,268272] use SIRT1 and mTOR pathways (Table 1.1). EPO utilizes components of the mTOR pathway, such as PRAS40 and Akt, to enhance cell survival [231,273275] and limit toxic cellular environments [249,276278]. EPO also plays a significant role as a potential cellular protectant during aging [279] and DM with the modulation of mTOR pathways, in part, to maintain cellular survival [34,84,96,97,268,270,280284]. In regard to SIRT1, EPO protects cells against toxic environments through SIRT1 [90,96,224,285]. EPO increases metabolic activity and maintains adipose energy homeostasis in adipocytes to protect against metabolic dysfunction through the combined activation of PPAR-α and SIRT1 [286]. EPO uses SIRT1 to modulate skeletal myogenic differentiation [287]. In central nervous system endothelial cells, EPO fosters the subcellular trafficking of SIRT1 to the nucleus to promote vascular cell protection and to prevent mitochondrial depolarization, cytochrome c release, BCL2-associated agonist of cell death (Bad) activity, and caspase activation [153]. EPO can protect human cardiomyocytes against mitochondrial dysfunction through the activation of SIRT1 during chemotherapy toxicity [107]. EPO also blocks the loss of neuronal cells in the brain through the upregulation of SIRT1 [288]. It is important to note that SIRT1 has an inverse relationship with mTOR [2,76,113,126,149,151,184,215,216]. SIRT1 activity results in neurite outgrowth and increased neuronal survival during nutrient limiting conditions with the inhibition of mTOR [289]. SIRT1 can promote tumor cell growth with autophagy activity that requires mTOR inhibition, illustrating that SIRT1 and autophagy pathways can be targets to control tumor cell growth [149]. During oxidative stress, SIRT1 can promote autophagy induction and the inhibition of mTOR to prevent mitochondrial dysfunction in embryonic stem cells [150] and can influence mitochondrial turnover through mitophagy [43]. During periods of hyperglycemia, SIRT1 blocks vascular cell injury during inhibition of mTOR activity [76]. Inhibition of mTOR with SIRT1 activation can increase cell survival for photoreceptor cells [115] and prevent cell senescence [151,290]. However, under some conditions that may involve dopaminergic neuronal cell loss, a balance in activities of SIRT1, mTOR, and forkhead transcription factors is necessary for neuroprotection [147]. This work suggests that there may be biological feedback pathways with mTOR, such as through AMPK inhibition, to prevent excessive mTOR activity. For example, if mTOR activity is unchecked during the inhibition of AMPK activity, mTOR and p70S6K can lead to glucose intolerance by inhibiting the insulin receptor substrate 1 (IRS-1) [291]. In addition, mTOR inhibition may reduce stroke infarct size during models of DM [187] and also can be necessary for maintaining a balance between pancreatic β-cell proliferation and cell size [292].

1.8 SIRT1, nicotinamide, and cellular metabolism As previously mentioned, the sirtuin deacetylation reaction generates nicotinamide as a product from the transfer of the acetyl residue from the acetyllysine residue of histones to the ADP-ribose moiety of NAD1 that leads to the generation of nicotinamide (Table 1.1). The agent and vitamin nicotinamide has a vital role during metabolic dysfunction and DM [12,44,95,96,293295]. Nicotinamide is the amide form of vitamin B3 (niacin) and it is obtained through synthesis in the body or as a dietary source and supplement, such as from animal sources or plants [295]. Nicotinic acid is the other form of the water-soluble vitamin B3 [296]. The primary form of niacin in dietary plant sources is nicotinic acid that is rapidly absorbed through the gastrointestinal epithelium [297].

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Nicotinamide is generated through the conversion of nicotinic acid in the liver or through the hydrolysis of the coenzyme ß-nicotinamide adenine dinucleotide (NAD1). Once nicotinamide is obtained in the body, it functions as the precursor for NAD1 [294,298]. It is also required for the synthesis of nicotinamide adenine dinucleotide phosphate (NADP1) [299]. Nicotinamide is changed to its mononucleotide form (NMN) with the enzyme nicotinic acid/nicotinamide adenylyltransferase yielding the dinucleotides NAAD1 and NAD1. NAAD1 converts to NAD1 through NAD1 synthase [300] or NAD1 can be synthesized through nicotinamide riboside kinase that phosphorylates nicotinamide riboside to NMN [301,302]. Nicotinamide through NAD1 can be directly utilized by cells to synthesize NAD1 [12,293295,303]. Nicotinamide participates in energy metabolism through the tricarboxylic acid cycle by utilizing NAD1 in the mitochondrial respiratory electron transport chain for the production of ATP, DNA synthesis, and DNA repair [304306]. Specific levels of NAD1 may be a critical factor for cell survival [303,307,308]. Nicotinamide offers protection usually in a specific concentration range [298]. Administration of nicotinamide in a range of 5.025.0 mmol/L can significantly protect neurons during oxidative stress injuries. This concentration range is similar to other injury paradigms in both animal models [309] and in cell culture models [294,310,311]. Elevated concentrations of nicotinamide in some experimental models may not offer protection and can be detrimental [312,313]. Yet increased administration of nicotinamide may be useful against tumorigenesis [314] and lead to apoptotic cell death in cancer cells [315,316]. In relation to cellular metabolism and DM, nicotinamide can lower insulin resistance and glucose release in combination with other factors to prevent the onset and progression of DM [317319] (Table 1.1). Nicotinamide may prevent skeletal muscle atrophy during DM [320], reduce mitochondrial stress through AMPK activation [321], and reduce inflammation of the brain during DM with the administration of niacin [322]. In animal models, nicotinamide can maintain normal fasting blood glucose with streptozotocin-induced DM [323,324] and block oxidative stress pathways that lead to cell death and apoptosis [311,325328]. In addition, nicotinamide can significantly improve glucose utilization, prevent excessive lactate production, and improve electrophysiologic capacity in ischemic animal models [329]. Oral nicotinamide administration (1200 mg/m2/day) has been shown to protect pancreatic β-cell function and prevents clinical disease in islet-cell antibody-positive first-degree relatives of type-1 DM [330]. Nicotinamide administration (25 mg/kg) in patients with recent onset type-1 DM combined with intensive insulin therapy for up to 2 years after diagnosis experienced significantly reduce HbA1c levels [331]. However, prolonged exposure of nicotinamide has been reported to result in impaired pancreatic β-cell function and cell growth [332,333]. Nicotinamide also may inhibit cytochromes P450 and hepatic metabolism [334]. As a result, the duration of nicotinamide administration may influence the efficacy of this agent since long-term administration also has been reported to support glucose intolerance in some animal models [307]. Since SIRT1 through the transfer of the acetyl residue from the acetyllysine residue of histones to the ADP-ribose moiety of NAD1 can lead to the production of nicotinamide, it is of interest to also note that nicotinamide is intimately linked to SIRT1 through autophagic pathways. Nicotinamide can promote the delayed induction of autophagy and subsequently decreased survival in cancer cells [335]. Mitochondrial autophagy (mitophagy) can result in an increased NAD1/NADH ratio during nicotinamide administration [132,307,336,337]. In addition, chronic administration of nicotinamide can lead to skeletal muscle lipotoxicity and glucose intolerance during autophagy activation [307]. Nicotinamide has been shown to prevent palmitate-induced hepatotoxicity via SIRT1-dependent induction of autophagy [338]. As an inhibitor of SIRT1, nicotinamide can limit cancer cell growth and in combination with chemotherapeutic agents lead to apoptotic cell death [154,339,340]. Furthermore, through SIRT1 inhibition, nicotinamide may exert antiinflammatory properties and affect the transcriptional regulation of inflammatory genes [341]. Additional studies suggest the nicotinamide, although an initial inhibitor of SIRT1, may subsequently promote SIRT activity as a result of the cellular conversion of nicotinamide to NAD1 [109].

1.9 Future considerations NCDs continue to impact a greater proportion of individuals throughout the world and affect both wealthy and low-income nations. Metabolic disorders, including DM, are a significant component of NCDs and currently lead to disability and death for an estimated 500 million individuals throughout the globe (Table 1.1). Metabolic disorders, such as DM, have marked deleterious effects since they can affect all organs of the body. Possibly more important is the observation that another 400 million individuals are believed to suffer from metabolic disease or are at risk for developing DM. In addition, obesity in the population represents an important risk factor for developing DM and can impair stem cell proliferation, aging, inflammation, and mitochondrial function through the generation of oxidative stress. In regard to financial costs to provide care for metabolic disorders, DM

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consumes more than 17% of the Gross Domestic Product in the United States and an estimated US$ 69 billion are consumed from reduced productivity as a result of DM. Metabolic disorders are complex in nature and present therapies only offer a minimal degree of protection since even under the best of circumstances, tight serum glucose control does not blunt the complications that can arise during DM. DM also has additional risk factors that include the development of neurodegenerative disorders and cognitive loss that can be compounded by hypertension, low education in early life, and tobacco use. The development of innovative and effective strategies is vital for the successful treatment of metabolic disorders. SIRT1 and its associated pathways with AMPK, mTOR, and the vitamin nicotinamide fill this essential need to offer exciting possibilities to address metabolic disease (Fig. 1.1). SIRT1, a histone deacetylase, is expressed in the brain, heart, liver, pancreas, skeletal muscle, spleen, and adipose tissues and during deacetylase reactions leads to the production of nicotinamide. SIRT1 activation can function to limit oxidative stress to potentially increase life span and limit disorders such as diabetic retinal injury and cognitive loss. SIRT1 activation blocks apoptotic cell death and, at times, can foster autophagy activation to protect embryonic stem cells during oxidative stress. In conjunction with pathways that involve PPAR-γ, PPAR-α, PGC-1α, PTP, and Akt, SIRT1 activity can improve insulin sensitivity, regulate glucose homeostasis, and limit the development of obesity. SIRT1 also has been shown to be present in POMC neurons and AgRP neurons in the arcuate nucleus of the hypothalamus to regulate food intake. SIRT1 relies upon AMPK to reduce insulin resistance and promote fatty acid oxidation and mitochondrial function. In turn, AMPK can promote the activation of SIRT1. SIRT1 and AMPK can work in association to prevent hyperglycemic cell death, maintain mitochondrial homeostasis, and reverse diabetic neuropathy symptoms. Through AMPK, induction of autophagy occurs that can offer cellular protection during elevated glucose and maintain glucose homeostasis. However, this upregulation of autophagy requires a fine balance during metabolic disorders. During periods of autophagy and metabolic dysfunction, loss of cardiac and liver tissue can occur in animal models, progenitor cell survival can become impaired, chronic inflammation can occur, and progression of atherosclerosis can ensue. SIRT1 also relies upon the mTOR pathway to oversee cellular metabolism. mTOR activation can limit cognitive loss during DM, prevent central nervous system microglial injury during oxidative stress and Aß toxicity, lessen diabetic neuropathy, and reduce ischemic stroke injury in conjunction with circadian clock genes. Loss of mTOR activity can impair β-cell function, insulin sensitivity, adipocyte differentiation, cellular survival, and insulin secretion. Furthermore, tropic factors, such as EPO, use mTOR to maintain adipose energy homeostasis and protect neuronal, vascular, and cardiac cells against mitochondrial dysfunction. Under several scenarios, SIRT1 holds an inverse relationship with mTOR to limit mTOR activity in order to foster neuronal and vascular survival, prevent cell senescence, and promote autophagy to block mitochondrial dysfunction and limit mitophagy. Given these observations with SIRT1 and mTOR, a biological feedback pathway between SIRT1 and mTOR may be FIGURE 1.1 Novel therapeutic pathways of SIRT1 for metabolic disease. Metabolic disorders, that include diabetes mellitus (DM), are an important component of noncommunicable diseases (NCDs) and can affect all organs and systems of the body. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and its associated pathways with AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), and nicotinamide offer new prospects for the development of treatments for metabolic disease. SIRT1 oversees metabolic function though a variety of mechanisms that involve insulin sensitivity and obesity, AMPK with preservation of β-cell function, mTOR with its subcomponents of mTORC1 and mTORC2 that can impact adipocyte differentiation and function through erythropoietin (EPO) to protect neuronal and vascular cell survival, and nicotinamide that can limit mitochondrial stress and preserve mitochondrial function. These pathways are closely tied to autophagy induction and apoptosis that ultimately can determine metabolic homeostasis.

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References

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necessary to achieve a high level of protection in the body and prevent excessive mTOR activity that may result in glucose intolerance, increased stroke size during DM, and loss of pancreatic β-cell proliferation. As a product of the SIRT1 deacetylation reaction, nicotinamide participates in energy metabolism through the tricarboxylic acid cycle by utilizing NAD1 in the mitochondrial respiratory electron transport chain and has a prominent role in overseeing cellular metabolism. Nicotinamide can reduce insulin resistance, maintain normal fasting blood glucose levels, and protect pancreatic β-cell function. Nicotinamide has been shown to block palmitate-induced hepatotoxicity through SIRT1-dependent induction of autophagy and may limit tumorigenesis through its inhibition of SIRT1. Yet the concentration of nicotinamide may be critical during metabolic disease, since prolonged or increased levels of nicotinamide administration may result in glucose intolerance and be toxic to cells. Furthermore, nicotinamide may also foster SIRT activity as a result of the cellular conversion of nicotinamide to NAD1. These studies highlight the importance of maintaining the proper balance of SIRT1 activity and nicotinamide levels to achieve an effective outcome for the treatment of metabolic disorders. It is clear that SIRT1 has a vital role in the maintenance of glucose homeostasis in the body and holds an intricate and complex relationship with AMPK, mTOR, and nicotinamide to maintain cellular metabolism and protect against toxic environments. In light of the fact that SIRT1 and its association with AMPK, mTOR, and nicotinamide can affect a number of organs throughout the body and oversee multiple biological process, additional studies should provide further insight for the development of new and robust strategies for the treatment of metabolic diseases that limit any unwarranted clinical outcomes.

Acknowledgments This research was supported by the following grants to Kenneth Maiese: American Diabetes Association, American Heart Association, NIH NIEHS, NIH NIA, NIH NINDS, and NIH ARRA.

References [1] Centers for Disease Control and Prevention. National diabetes statistics report, 2020. 2020;CS 314227-A:130. [2] Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol 2020;13(1):2334. [3] Speer H, D’Cunha NM, Alexopoulos NI, McKune AJ, Naumovski N. Anthocyanins and human health—a focus on oxidative stress, inflammation and disease. Antioxidants (Basel) 2020;9(5). [4] International Diabetes Federation. Diabetes. IDF diabetes atlas. 9th ed.; 2019. [5] Maiese K. New insights for oxidative stress and diabetes mellitus. Oxid Med Cell Longev 2015;2015:875961. [6] Hu Z, Jiao R, Wang P, Zhu Y, Zhao J, De Jager P, et al. Shared causal paths underlying Alzheimer’s dementia and type 2 diabetes. Sci Rep 2020;10(1):4107. [7] Schiano C, Benincasa G, Franzese M, Della Mura N, Pane K, Salvatore M, et al. Epigenetic-sensitive pathways in personalized therapy of major cardiovascular diseases. Pharmacol Ther 2020;210:107514. [8] Maiese K. Targeting the core of neurodegeneration: FoxO, mTOR, and SIRT1. Neural Reg Res 2021;16(3):44855. [9] World Health Organization. Description of the global burden of NCDs, their risk factors and determinants. Glob Status Rep Noncommunicable Dis 2010;2011:1176. [10] World Health Organization. Global action plan on the public health response to dementia 20172025. WHO 2017, p. 1-44. [11] Maiese K. Sirtuins: developing innovative treatments for aged-related memory loss and Alzheimer’s disease. Curr Neurovasc Res 2018;15(4):36771. [12] Maiese K. New insights for nicotinamide: metabolic disease, autophagy, and mTOR. Front Biosci (Landmark Ed) 2020;25:192573. [13] National Center for Health Statistics. National vital statisitcs system. National Center for Health Statistics Fact Sheet 2019, p. 12. [14] Maiese K. Cutting through the complexities of mTOR for the treatment of stroke. Curr Neurovasc Res 2014;11(2):17786. [15] Minino AM. Death in the United States, 2011. NCHS Data Brief 2013;(115):18. [16] Hayutin A. Global demographic shifts create challenges and opportunities. PREA Q 2007;4653. [17] Maiese K. SIRT1 and stem cells: in the forefront with cardiovascular disease, neurodegeneration and cancer. World J Stem Cell 2015; 7(2):23542. [18] Maiese K. Programming apoptosis and autophagy with novel approaches for diabetes mellitus. Curr Neurovasc Res 2015;12(2):17388. [19] Diamanti-Kandarakis E, Datillo M, Macut D, Duntas LH, Gonos E, Goulis D, et al. Mechanisms in endocrinology: aging and anti-aging endocrinology: a combo - endocrinology overview. Eur J Endocrinol 2017;176(6):R283308. [20] Fann DY, Ng GY, Poh L, Arumugam TV. Positive effects of intermittent fasting in ischemic stroke. Exp Gerontol 2017;89:93102. [21] Lushchak O, Strilbytska O, Piskovatska V, Storey KB, Koliada A, Vaiserman A. The role of the TOR pathway in mediating the link between nutrition and longevity. Mech Ageing Dev 2017;164:12738. [22] Maiese K. Moving to the rhythm with clock (circadian) genes, autophagy, mTOR, and SIRT1 in degenerative disease and cancer. Curr Neurovasc Res 2017;14(3):299304. [23] Stefanatos R, Sanz A. The role of mitochondrial ROS in the aging brain. FEBS Lett 2018;592(5):74358. [24] Quesada I, de Paola M, Torres-Palazzolo C, Camargo A, Ferder L, Manucha W, et al. Effect of garlic’s active constituents in inflammation, obesity and cardiovascular disease. Curr Hypertens Rep 2020;22(1):6.

I. Sirtuins and metabolic disease

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[25] Ali T, Rahman SU, Hao Q, Li W, Liu Z, Ali Shah F, et al. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation. J Pineal Res 2020;69(2):e12667. [26] Doroftei B, Ilie OD, Cojocariu RO, Ciobica A, Maftei R, Grab D, et al. Minireview exploring the biological cycle of vitamin B3 and its influence on oxidative stress: further molecular and clinical aspects. Molecules 2020;25(15):3323. [27] Klimontov VV, Bulumbaeva DM, Fazullina ON, Lykov AP, Bgatova NP, Orlov NB, et al. Circulating Wnt1-inducible signaling pathway protein-1 (WISP-1/CCN4) is a novel biomarker of adiposity in subjects with type 2 diabetes. J Cell Commun Signal 2020;14 (1):1019. [28] Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res 2016;11(3):37285. [29] Maiese K. Impacting dementia and cognitive loss with innovative strategies: mechanistic target of rapamycin, clock genes, circular noncoding ribonucleic acids, and Rho/Rock. Neural Regen Res 2019;14(5):7734. [30] Haldar SR, Chakrabarty A, Chowdhury S, Haldar A, Sengupta S, Bhattacharyya M. Oxidative stress-related genes in type 2 diabetes: association analysis and their clinical impact. Biochem. Genet 2015;53(46):93119. [31] Jia G, Aroor AR, Martinez-Lemus LA, Sowers JR. Invited review: over-nutrition, mTOR signaling and cardiovascular diseases. Am J Physiol Regul Integr Comp Physiol 2014;307(10):R1198206. [32] Ye Q, Fu JF. Paediatric type 2 diabetes in China-Pandemic, progression, and potential solutions. Pediatric Diabetes 2018;19(1):2735. [33] Harris MI, Eastman RC. Early detection of undiagnosed diabetes mellitus: a US perspective. Diabetes Metab Res Rev 2000; 16(4):2306. [34] Maiese K. mTOR: driving apoptosis and autophagy for neurocardiac complications of diabetes mellitus. World J Diabetes 2015; 6(2):21724. [35] Maiese K, Chong ZZ, Shang YC. Mechanistic insights into diabetes mellitus and oxidative stress. Curr Med Chem 2007;14(16):172938. [36] Maiese K. Heightened attention for Wnt signaling in diabetes mellitus. Curr Neurovasc Res 2020;17(3):21517. [37] Barchetta I, Cimini FA, Ciccarelli G, Baroni MG, Cavallo MG. Sick fat: the good and the bad of old and new circulating markers of adipose tissue inflammation. J Endocrinol Invest 2019;42(11):125772. [38] Maiese K. Erythropoietin and diabetes mellitus. World J Diabetes 2015;6(14):125973. [39] Wang AR, Yan XQ, Zhang C, Du CQ, Long WJ, Zhan D, et al. Characterization of Wnt1-inducible signaling pathway protein-1 in obese children and adolescents. Curr Med Sci 2018;38(5):86874. [40] Liu L, Hu J, Yang L, Wang N, Liu Y, Wei X, et al. Association of WISP1/CCN4 with risk of overweight and gestational diabetes mellitus in Chinese pregnant women. Dis Markers 2020;2020:4934206. [41] Maiese K. Prospects and perspectives for WISP1 (CCN4) in diabetes mellitus. Curr Neurovasc Res 2020;17(3):32731. [42] Yamashima T, Ota T, Mizukoshi E, Nakamura H, Yamamoto Y, Kikuchi M, et al. Intake of ω-6 polyunsaturated fatty acid-rich vegetable oils and risk of lifestyle diseases. Adv Nutr 2020;11(6):1489509. [43] Yang J, Suo H, Song J. Protective role of mitoquinone against impaired mitochondrial homeostasis in metabolic syndrome. Crit Rev Food Sci Nutr 2020;20:119. [44] Maiese K, Chong ZZ, Shang YC, Hou J. Novel avenues of drug discovery and biomarkers for diabetes mellitus. J Clin Pharmacol 2011; 51(2):12852. [45] Cernea M, Tang W, Guan H, Yang K. Wisp1 mediates Bmp3-stimulated mesenchymal stem cell proliferation. J Mol Endocrinol 2016; 56(1):3946. [46] Curjuric I, Imboden M, Bridevaux PO, Gerbase MW, Haun M, Keidel D, et al. Common SIRT1 variants modify the effect of abdominal adipose tissue on aging-related lung function decline. Age (Dordr) 2016;38(3):52. [47] Hill JH, Solt C, Foster MT. Obesity associated disease risk: the role of inherent differences and location of adipose depots. Hormone Mol Biol Clin Invest 2018;33(2). Available from: https://doi.org/10.1515/hmbci-2018-0012. [48] Liu Z, Gan L, Zhang T, Ren Q, Sun C. Melatonin alleviates adipose inflammation through elevating alpha-ketoglutarate and diverting adipose-derived exosomes to macrophages in mice. J Pineal Res 2018;64(1):12455. [49] Maiese K. Picking a bone with WISP1 (CCN4): new strategies against degenerative joint disease. J Transl Sci 2016;1(3):835. [50] Mehta J, Rayalam S, Wang X. Cytoprotective effects of natural compounds against oxidative stress. Antioxidants (Basel) 2018;7(10). [51] Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 2005;75(3):20746. [52] Centers for Medicare and Medicaid Services. National health expenditure projections 20182027. ,wwwcmsgov.; 2019. [53] Maiese K. Dysregulation of metabolic flexibility: the impact of mTOR on autophagy in neurodegenerative disease. Int Rev Neurobiol 2020;155:135. [54] Albiero M, Poncina N, Tjwa M, Ciciliot S, Menegazzo L, Ceolotto G, et al. Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1. Diabetes 2014;63(4):135365. [55] Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr 2014;6(1):80. [56] Gomez-Brouchet A, Blaes N, Mouledous L, Fourcade O, Tack I, Frances B, et al. Beneficial effects of levobupivacaine regional anaesthesia on postoperative opioid induced hyperalgesia in diabetic mice. J Transl Med 2015;13(1):208. [57] Atef MM, El-Sayed NM, Ahmed AAM, Mostafa YM. Donepezil improves neuropathy through activation of AMPK signalling pathway in streptozotocin-induced diabetic mice. Biochem Pharmacol 2019;159:110. [58] Dong J, Li H, Bai Y, Wu C. Muscone ameliorates diabetic peripheral neuropathy through activating AKT/mTOR signalling pathway. J Pharm Pharmacol 2019;71(11):170613. [59] Caberlotto L, Nguyen TP, Lauria M, Priami C, Rimondini R, Maioli S, et al. Cross-disease analysis of Alzheimer’s disease and type-2 diabetes highlights the role of autophagy in the pathophysiology of two highly comorbid diseases. Sci Rep 2019;9(1):3965. [60] Su M, Naderi K, Samson N, Youssef I, Fulop L, Bozso Z, et al. Mechanisms associated with type 2 diabetes as a risk factor for Alzheimer-related pathology. Mol Neurobiol 2019;56(8):581534.

I. Sirtuins and metabolic disease

References

15

[61] Hsieh CF, Liu CK, Lee CT, Yu LE, Wang JY. Acute glucose fluctuation impacts microglial activity, leading to inflammatory activation or self-degradation. Sci Rep 2019;9(1):840. [62] Maiese K, Chong ZZ, Shang YC, Hou J. FoxO proteins: cunning concepts and considerations for the cardiovascular system. Clin Sci (Lond) 2009;116(3):191203. [63] Tang PC, Ng YF, Ho S, Gyda M, Chan SW. Resveratrol and cardiovascular health—promising therapeutic or hopeless illusion? Pharmacol Res 2014;90:88115. [64] Xiang L, Mittwede PN, Clemmer JS. Glucose homeostasis and cardiovascular alterations in diabetes. Compr Physiol 2015; 5(4):181539. [65] Xu YJ, Tappia PS, Neki NS, Dhalla NS. Prevention of diabetes-induced cardiovascular complications upon treatment with antioxidants. Heart Fail Rev 2014;19(1):11321. [66] Yao T, Fujimura T, Murayama K, Okumura K, Seko Y. Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in high glucose-induced apoptosis in rat cardiac myocytes and murine pancreatic beta-cells. Cells 2017;6(4):35. [67] Fan X, Zhao Z, Wang D, Xiao J. Glycogen synthase kinase-3 as a key regulator of cognitive function. Acta Biochimica et Biophysica Sinica 2020;52(3):21930. [68] Hadamitzky M, Herring A, Kirchhof J, Bendix I, Haight MJ, Keyvani K, et al. Repeated systemic treatment with rapamycin affects behavior and amygdala protein expression in rats. Int J Neuropsychopharmacol 2018;21(6):592602. [69] Ignacio ZM, Reus GZ, Arent CO, Abelaira HM, Pitcher MR, Quevedo J. New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs. Br J Clin Pharmacol 2016;82(5):128090. [70] Di Rosa M, Malaguarnera L. Chitotriosidase: a new inflammatory marker in diabetic complications. Pathobiology 2016;83(4):21119. [71] Maiese K, Chong ZZ, Hou J, Shang YC. Erythropoietin and oxidative stress. Curr Neurovasc Res 2008;5(2):12542. [72] Tulsulkar J, Nada SE, Slotterbeck BD, McInerney MF, Shah ZA. Obesity and hyperglycemia lead to impaired post-ischemic recovery after permanent ischemia in mice. Obesity 2015;24(2):41723 (Silver Spring, Md). [73] Xiao FH, He YH, Li QG, Wu H, Luo LH, Kong QP. A genome-wide scan reveals important roles of DNA methylation in human longevity by regulating age-related disease genes. PLoS One 2015;10(3):e0120388. [74] Arildsen L, Andersen JV, Waagepetersen HS, Nissen JBD, Sheykhzade M. Hypermetabolism and impaired endothelium-dependent vasodilation in mesenteric arteries of type 2 diabetes mellitus db/db mice. Diabetes Vasc Dis Res: Off J Int Soc Diabetes Vasc Dis 2019; 16(6):53948. 1479164119865885. [75] Ding S, Zhu Y, Liang Y, Huang H, Xu Y, Zhong C. Circular RNAs in vascular functions and diseases. Adv Exp Med Biol 2018;1087:28797. [76] Pal PB, Sonowal H, Shukla K, Srivastava SK, Ramana KV. Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/ AMPK-alpha1/mTOR pathway. J Mol Endocrinol 2019;63(1):1125. [77] Alexandru N, Popov D, Georgescu A. Platelet dysfunction in vascular pathologies and how can it be treated. Thromb Res 2012; 129(2):11626. [78] Chiu SC, Chao CY, Chiang EI, Syu JN, Rodriguez RL, Tang FY. N-3 polyunsaturated fatty acids alleviate high glucose-mediated dysfunction of endothelial progenitor cells and prevent ischemic injuries both in vitro and in vivo. J Nutr Biochem 2017;42:17281. [79] Maiese K. Disease onset and aging in the world of circular RNAs. J Transl Sci 2016;2(6):3279. [80] Maiese K, Chong ZZ, Shang YC, Hou J. Rogue proliferation versus restorative protection: where do we draw the line for Wnt and forkhead signaling? Expert Opin Ther Targets 2008;12(7):90516. [81] Maiese K, Li F, Chong ZZ, Shang YC. The Wnt signaling pathway: aging gracefully as a protectionist? Pharmacol Ther 2008; 118(1):5881. [82] Perez-Hernandez N, Vargas-Alarcon G, Posadas-Sanchez R, Martinez-Rodriguez N, Tovilla-Zarate CA, Rodriguez-Cortes AA, et al. PHACTR1 gene polymorphism is associated with increased risk of developing premature coronary artery disease in Mexican population. Int J Environ Res Public Health 2016;13(8):803. [83] Thackeray JT, Radziuk J, Harper ME, Suuronen EJ, Ascah KJ, Beanlands RS, et al. Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia. Cardiovasc Diabetol 2011;10:75. [84] Maiese K. Novel applications of trophic factors, Wnt and WISP for neuronal repair and regeneration in metabolic disease. Neural Regen Res 2015;10(4):51828. [85] Mishra M, Duraisamy AJ, Kowluru RA. Sirt1- A guardian of the development of diabetic retinopathy. Diabetes 2018;67(4):74554. [86] Ponnalagu M, Subramani M, Jayadev C, Shetty R, Das D. Retinal pigment epithelium-secretome: a diabetic retinopathy perspective. Cytokine 2017;95:12635. [87] Kell DB, Pretorius E. No effects without causes: the iron dysregulation and dormant microbes hypothesis for chronic, inflammatory diseases. Biological Reviews of the Cambridge Philosophical Society 2018;93(3):151857. [88] Lin X, Zhang N. Berberine: pathways to protect neurons. Phytotherapy research: PTR; 2018. [89] Maiese K. FoxO transcription factors and regenerative pathways in diabetes mellitus. Curr Neurovasc Res 2015;12(4):40413. [90] Maiese K, Chong ZZ, Shang YC, Wang S. Translating cell survival and cell longevity into treatment strategies with SIRT1. Rom J Morphol Embryol 2011;52(4):117385. [91] Woodhams L, Al-Salami H. The roles of bile acids and applications of microencapsulation technology in treating Type 1 diabetes mellitus. Ther. Deliv 2017;8(6):4019. [92] Zhao Y, Scott NA, Fynch S, Elkerbout L, Wong WW, Mason KD, et al. Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes. Diabetologia 2015;58(1):1408. [93] Maiese K. The mechanistic target of rapamycin (mTOR): novel considerations as an antiviral treatment. Curr Neurovasc Res 2020; 17(3):3327.

I. Sirtuins and metabolic disease

16

1. Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

[94] Guo T, Liu T, Sun Y, Liu X, Xiong R, Li H, et al. Sonodynamic therapy inhibits palmitate-induced beta cell dysfunction via PINK1/ Parkin-dependent mitophagy. Cell Death Dis 2019;10(6):457. [95] Klimova N, Kristian T. Multi-targeted effect of nicotinamide mononucleotide on brain bioenergetic metabolism. Neurochem Res 2019; 44(10):22807. [96] Maiese K, Chong ZZ, Shang YC, Wang S. Novel directions for diabetes mellitus drug discovery. Expert Opin Drug Discovery 2013; 8(1):3548. [97] Othman MAM, Rajab E, AlMubarak A, AlNaisar M, Bahzad N, Kamal A. Erythropoietin protects against cognitive impairment and hippocampal neurodegeneration in diabetic mice. Behav Sci (Basel, Switz) 2018;9(1):4. [98] Yelumalai S, Giribabu N, Karim K, Omar SZ, Salleh NB. In vivo administration of quercetin ameliorates sperm oxidative stress, inflammation, preserves sperm morphology and functions in streptozotocin-nicotinamide induced adult male diabetic rats. Arch Med Sci: AMS 2019;15(1):2409. [99] Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med 2012;172(10):7619. [100] Lee JH, Lee JH, Jin M, Han SD, Chon GR, Kim IH, et al. Diet control to achieve euglycemia induces significant loss of heart and liver weight via increased autophagy compared with ad libitum diet in diabetic rats. Exp Mol Med 2014;46:e111. [101] Maiese K. MicroRNAs for the treatment of dementia and Alzheimer’s disease. Curr Neurovasc Res 2019;16(1):12. [102] Chen F, Liu Z, Peng W, Gao Z, Ouyang H, Yan T, et al. Activation of EphA4 induced by EphrinA1 exacerbates disruption of the bloodbrain barrier following cerebral ischemia-reperfusion via the Rho/ROCK signaling pathway. Exp Ther Med 2018;16(3):26518. [103] Maiese K. Dampening the progression of dementia. Curr Neurovasc Res 2018;15(2):93. [104] Ong WY, Wu YJ, Farooqui T, Farooqui AA. Qi Fu Yin-a Ming Dynasty prescription for the treatment of dementia. Mol Neurobiol 2018;55(9):7389400. [105] Charles S, Raj V, Arokiaraj J, Mala K. Caveolin1/protein arginine methyltransferase1/sirtuin1 axis as a potential target against endothelial dysfunction. Pharmacol Res 2017;119:111. [106] Chong ZZ, Shang YC, Wang S, Maiese K. SIRT1: new avenues of discovery for disorders of oxidative stress. Expert Opin Ther Targets 2012;16(2):16778. [107] Cui L, Guo J, Zhang Q, Yin J, Li J, Zhou W, et al. Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicininduced mitochondrial dysfunction and toxicity. Toxicol Lett 2017;275:2838. [108] Geng C, Xu H, Zhang Y, Gao Y, Li M, Liu X, et al. Retinoic acid ameliorates high-fat diet-induced liver steatosis through sirt1. Science China Life Sci 2017;60(11):123441. [109] Hwang ES, Song SB. Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cell Mol Life Sci 2017; 74(18):334762. [110] Maiese K. FoxO proteins in the nervous system. Anal Cell Pathol (Amst) 2015;2015:569392. [111] Maiese K. Forkhead transcription factors: new considerations for alzheimer’s disease and dementia. J Transl Sci 2016;2(4):2417. [112] Maiese K. Harnessing the power of SIRT1 and non-coding RNAs in vascular disease. Curr Neurovasc Res 2017;14(1):828. [113] Maiese K. The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders. Biochem Soc Trans 2018;46(2):35160. [114] Maiese K. Novel treatment strategies for the nervous system: circadian clock genes, non-coding RNAs, and forkhead transcription factors. Curr Neurovasc Res 2018;15(1):8191. [115] Pan YR, Song JY, Fan B, Wang Y, Che L, Zhang SM, et al. mTOR may interact with PARP-1 to regulate visible light-induced parthanatos in photoreceptors. Cell Commun Signal 2020;18(1):27. [116] Tang YL, Zhang CG, Liu H, Zhou Y, Wang YP, Li Y, et al. Ginsenoside Rg1 inhibits cell proliferation and induces markers of cell senescence in CD34 1 CD38- Leukemia stem cells derived from KG1alpha acute myeloid Leukemia cells by activating the Sirtuin 1 (SIRT1)/ Tuberous Sclerosis Complex 2 (TSC2) signaling pathway. Med Sci Monit 2020;26:e918207. [117] Zhang Y, Zhu X, Wang G, Chen L, Yang H, He F, et al. Melatonin rescues the Ti particle-impaired osteogenic potential of bone marrow mesenchymal stem cells via the SIRT1/SOD2 signaling pathway. Calcif Tissue Int 2020;107(5):47488. [118] Cacabelos R, Carril JC, Cacabelos N, Kazantsev AG, Vostrov AV, Corzo L, et al. Sirtuins in Alzheimer’s disease: SIRT2-related GenoPhenotypes and Implications for PharmacoEpiGenetics. Int J Mol Sci 2019;20(5):1249. [119] Bruckbauer A, Banerjee J, Cao Q, Cui X, Jing J, Zha L, et al. Leucine-nicotinic acid synergy stimulates AMPK/Sirt1 signaling and regulates lipid metabolism and lifespan in Caenorhabditis elegans, and hyperlipidemia and atherosclerosis in mice. Am J Cardiovascular Dis 2017;7(2):3347. [120] Chong ZZ, Wang S, Shang YC, Maiese K. Targeting cardiovascular disease with novel SIRT1 pathways. Future Cardiol 2012;8(1):89100. [121] Li WY, Ren JH, Tao NN, Ran LK, Chen X, Zhou HZ, et al. The SIRT1 inhibitor, nicotinamide, inhibits hepatitis B virus replication in vitro and in vivo. Arch Virol 2016;161(3):62130. [122] Hou J, Chong ZZ, Shang YC, Maiese K. FoxO3a governs early and late apoptotic endothelial programs during elevated glucose through mitochondrial and caspase signaling. Mol Cell Endocrinol 2010;321(2):194206. [123] Hou J, Chong ZZ, Shang YC, Maiese K. Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation. Curr Neurovasc Res 2010;7(2):95112. [124] Maiese K. Healing the heart with sirtuins and mammalian forkhead transcription factors. Curr Neurovasc Res 2020;17(1):12. [125] Hsu YC, Wu YT, Tsai CL, Wei YH. Current understanding and future perspectives of the roles of sirtuins in the reprogramming and differentiation of pluripotent stem cells. Exp Biol Med (Maywood) 2018;243(6):56375. [126] Maiese K. Taking aim at Alzheimer’s disease through the mammalian target of rapamycin. Ann Med 2014;46(8):58796. [127] Mahmoudi N, Kiasalari Z, Rahmani T, Sanaierad A, Afshin-Majd S, Naderi G, et al. Diosgenin attenuates cognitive impairment in streptozotocin-induced diabetic rats: underlying mechanisms. Neuropsychobiology 2020;11:111. [128] Maiese K, Shang YC, Chong ZZ, Hou J. Diabetes mellitus: channeling care through cellular discovery. Curr Neurovasc Res 2010; 7(1):5964.

I. Sirtuins and metabolic disease

References

17

[129] Balan V, Miller GS, Kaplun L, Balan K, Chong ZZ, Li F, et al. Life span extension and neuronal cell protection by Drosophila nicotinamidase. J Biol Chem 2008;283(41):2781019. [130] Chong ZZ, Maiese K. Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways. Curr Neurovasc Res 2008;5(3):15970. [131] Lamoke F, Shaw S, Yuan J, Ananth S, Duncan M, Martin P, et al. Increased oxidative and nitrative stress accelerates aging of the retinal vasculature in the diabetic retina. PLoS One 2015;10(10):e0139664. [132] Maiese K. The bright side of reactive oxygen species: lifespan extension without cellular demise. J Transl Sci 2016;2(3):1857. [133] Poljsak B, Milisav I. NAD( 1 ) as the link between oxidative stress, inflammation, caloric restriction, exercise, DNA repair, longevity and health span. Rejuvenation Res 2016;19(5):40615. [134] Wang XL, Li T, Li JH, Miao SY, Xiao XZ. The effects of resveratrol on inflammation and oxidative stress in a rat model of chronic obstructive pulmonary disease. Molecules 2017;22(9):1529. [135] Zhang XS, Wu Q, Wu LY, Ye ZN, Jiang TW, Li W, et al. Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats. Cell Death Dis 2016;7(10):e2416. [136] Khan M, Ullah R, Rehman SU, Shah SA, Saeed K, Muhammad T, et al. 17beta-estradiol modulates SIRT1 and halts oxidative stressmediated cognitive impairment in a male aging mouse model. Cells 2019;8(8):928. [137] Qian S, Gu J, Dai W, Jin N, Chu D, Huang Q, et al. Sirt1 enhances tau exon 10 inclusion and improves spatial memory of Htau mice. Aging (Albany NY) 2018;10(9):2498510. [138] Chong ZZ, Li F, Maiese K. Attempted cell cycle induction in post-mitotic neurons occurs in early and late apoptotic programs through Rb, E2F1, and Caspase 3. Curr Neurovasc Res 2006;3(1):2539. [139] Folch J, Junyent F, Verdaguer E, Auladell C, Pizarro JG, Beas-Zarate C, et al. Role of cell cycle re-entry in neurons: a common apoptotic mechanism of neuronal cell death. Neurotox Res 2012;22(3):195207. [140] Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, et al. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem 2009;110(5):144556. [141] Guo P, Wang D, Wang X, Feng H, Tang Y, Sun R, et al. Effect and mechanism of fuzhisan and donepezil on the sirtuin 1 pathway and amyloid precursor protein metabolism in PC12 cells. Mol Med Rep 2016;13(4):353946. [142] Li MZ, Zheng LJ, Shen J, Li XY, Zhang Q, Bai X, et al. SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes. Neural Regen Res 2018;13(11):200513. [143] Sun Q, Jia N, Wang W, Jin H, Xu J, Hu H. Activation of SIRT1 by curcumin blocks the neurotoxicity of amyloid-beta25-35 in rat cortical neurons. Biochem Biophys Res Commun 2014;448(1):8994. [144] Arunachalam G, Lakshmanan AP, Samuel SM, Triggle CR, Ding H. Molecular interplay between microRNA-34a and sirtuin1 in hyperglycemia-mediated impaired angiogenesis in endothelial cells: effects of metformin. J Pharmacol Exp Ther 2016; 356(2):31423. [145] Saboori S, Koohdani F, Nematipour E, Yousefi Rad E, Saboor-Yaraghi AA, Javanbakht MH, et al. Beneficial effects of omega-3 and vitamin E coadministration on gene expression of SIRT1 and PGC1alpha and serum antioxidant enzymes in patients with coronary artery disease. Nutrition, Metabolism, Cardiovascular Dis: NMCD 2016;26(6):48994. [146] Yu L, Liang H, Dong X, Zhao G, Jin Z, Zhai M, et al. Reduced silent information regulator 1 signaling exacerbates myocardial ischemiareperfusion injury in type 2 diabetic rats and the protective effect of melatonin. J Pineal Res 2015;59(3):37690. [147] Zhang C, Li C, Chen S, Li Z, Ma L, Jia X, et al. Hormetic effect of panaxatriol saponins confers neuroprotection in PC12 cells and zebrafish through PI3K/AKT/mTOR and AMPK/SIRT1/FOXO3 pathways. Sci Rep 2017;7:41082. [148] Ghiasi R, Naderi R, Sheervalilou R, Alipour MR. Swimming training by affecting the pancreatic Sirtuin1 (SIRT1) and oxidative stress, improves insulin sensitivity in diabetic male rats. Hormone Mol Biol Clin Invest 2019;40(3). Available from: https://doi.org/10.1515/ hmbci-2019-0011. [149] Mu N, Lei Y, Wang Y, Wang Y, Duan Q, Ma G, et al. Inhibition of SIRT1/2 upregulates HSPA5 acetylation and induces pro-survival autophagy via ATF4-DDIT4-mTORC1 axis in human lung cancer cells. Apoptosis 2019;24(910):798811. [150] Ou X, Lee MR, Huang X, Messina-Graham S, Broxmeyer HE. SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cell 2014;32(5):118394. [151] Zhang H, Yang X, Pang X, Zhao Z, Yu H, Zhou H. Genistein protects against ox-LDL-induced senescence through enhancing SIRT1/ LKB1/AMPK-mediated autophagy flux in HUVECs. Mol Cell Biochem 2019;455(1). [152] Fong Y, Lin YC, Wu CY, Wang HM, Lin LL, Chou HL, et al. The antiproliferative and apoptotic effects of sirtinol, a sirtuin inhibitor on human lung cancer cells by modulating Akt/beta-catenin-Foxo3a axis. Sci World J 2014;2014:937051. [153] Hou J, Wang S, Shang YC, Chong ZZ, Maiese K. Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress. Curr Neurovasc Res 2011;8(3):22035. [154] Wang T, Cui H, Ma N, Jiang Y. Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis. Oncol Lett 2013;6(2):6004. [155] Du G, Song Y, Zhang T, Ma L, Bian N, Chen X, et al. Simvastatin attenuates TNFalphainduced apoptosis in endothelial progenitor cells via the upregulation of SIRT1. Int J Mol Med 2014;34(1):17782. [156] Paschalaki KE, Starke RD, Hu Y, Mercado N, Margariti A, Gorgoulis VG, et al. Dysfunction of endothelial progenitor cells from smokers and chronic obstructive pulmonary disease patients due to increased DNA damage and senescence. Stem Cell 2013;31 (12):281326. [157] Guan XH, Liu XH, Hong X, Zhao N, Xiao YF, Wang LF, et al. CD38 deficiency protects the heart from ischemia/reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. Oxid Med Cell Longev 2016;2016:7410257. [158] Bellet MM, Masri S, Astarita G, Sassone-Corsi P, Della Fazia MA, Servillo G. Histone deacetylase SIRT1 controls proliferation, circadian rhythm, and lipid metabolism during liver regeneration in mice. J Biol Chem 2016;291(44):2331829. [159] Zhao D, Sun X, Lv S, Sun M, Guo H, Zhai Y, et al. Salidroside attenuates oxidized lowdensity lipoproteininduced endothelial cell injury via promotion of the AMPK/SIRT1 pathway. Int J Mol Med 2019;43(6):227990.

I. Sirtuins and metabolic disease

18

1. Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

[160] Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004;429(6993):7716. [161] Han L, Zhou R, Niu J, McNutt MA, Wang P, Tong T. SIRT1 is regulated by a PPARγ-SIRT1 negative feedback loop associated with senescence. Nucleic Acids Res 2010;38(21):745871. [162] Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006;444(7117):33742. [163] Sasaki T, Kitamura T. Roles of FoxO1 and Sirt1 in the central regulation of food intake. Endocr J 2010;57(11):93946. [164] Maiese K, Chong ZZ, Shang YC. OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. Trends Mol Med 2008;14(5):21927. [165] Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA, Mostoslavsky R, et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 2010;12(1):7887. [166] Sugden MC, Caton PW, Holness MJ. PPAR control: it’s SIRTainly as easy as PGC. J Endocrinol 2010;204(2):93104. [167] Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434(7029):11318. [168] Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 2009;9(4):32738. [169] Caron AZ, He X, Mottawea W, Seifert EL, Jardine K, Dewar-Darch D, et al. The SIRT1 deacetylase protects mice against the symptoms of metabolic syndrome. FASEB J 2014;28(3):130616. [170] Xue P, Zhao J, Zheng A, Li L, Chen H, Tu W, et al. Chrysophanol alleviates myocardial injury in diabetic db/db mice by regulating the SIRT1/HMGB1/NF-kappaB signaling pathway. Exp Ther Med 2019;18(6):440612. [171] Chen YR, Fang SR, Fu YC, Zhou XH, Xu MY, Xu WC. Calorie restriction on insulin resistance and expression of SIRT1 and SIRT4 in rats. Biochem Cell Biol 2010;88(4):71522. [172] Sun C, Zhang F, Ge X, Yan T, Chen X, Shi X, et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 2007;6(4):30719. [173] Li Y, Xu S, Giles A, Nakamura K, Lee JW, Hou X, et al. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. Faseb J 2011;25(5):166479. [174] Frojdo S, Durand C, Molin L, Carey AL, El-Osta A, Kingwell BA, et al. Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1. Mol Cell Endocrinol 2011;335(2):16676. [175] Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 2006;4(2):e31. [176] Vetterli L, Brun T, Giovannoni L, Bosco D, Maechler P. Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through Sirt1 dependent mechanism. J Biol Chem 2011;286(8):604960. [177] Alicea-Velazquez NL, Boggon TJ. SHP family protein tyrosine phosphatases adopt canonical active-site conformations in the apo and phosphate-bound states. Protein Peptide Lett 2013;20(9):103948. [178] Chong ZZ, Lin SH, Kang JQ, Maiese K. The tyrosine phosphatase SHP2 modulates MAP kinase p38 and caspase 1 and 3 to foster neuronal survival. Cell Mol Neurobiol 2003;23(45):56178. [179] Chong ZZ, Maiese K. The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histol Histopathol 2007;22(11):125167. [180] Geldman A, Pallen CJ. Protein tyrosine phosphatases in mast cell signaling. Methods Mol Biol (Clifton, NJ) 2015;1220:26986. [181] Lee DK, Park JY, Yoo JC, Byun EH, Bae YJ, Lee YS, et al. PTPN6 regulates the cell-surface expression of TRPM4 channels in HEK293 cells. Pflugers Arch 2018;470(10):144958. [182] Xu E, Schwab M, Marette A. Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance. Rev Endocr Metab Disord 2014;15(1):7997. [183] Castano D, Larequi E, Belza I, Astudillo AM, Martinez-Anso E, Balsinde J, et al. Cardiotrophin-1 eliminates hepatic steatosis in obese mice by mechanisms involving AMPK activation. J hepatology 2014;60(5):101725. [184] Maiese K. Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. Br J Clin Pharmacol 2016; 82(5):124566. [185] Liu Y, Palanivel R, Rai E, Park M, Gabor TV, Scheid MP, et al. Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high fat diet feeding in mice. Diabetes 2014;64(1):3648. [186] Moroz N, Carmona JJ, Anderson E, Hart AC, Sinclair DA, Blackwell TK. Dietary restriction involves NAD1-dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 2014;13(6):107585. [187] Liu P, Yang X, Hei C, Meli Y, Niu J, Sun T, et al. Rapamycin reduced ischemic brain damage in diabetic animals is associated with suppressions of mTOR and ERK1/2 signaling. Int J Biol Sci 2016;12(8):103240. [188] Du LL, Chai DM, Zhao LN, Li XH, Zhang FC, Zhang HB, et al. AMPK activation ameliorates Alzheimer’s disease-like pathology and spatial memory impairment in a streptozotocin-induced Alzheimer’s disease model in rats. J Alzheimers Dis 2015;43(3):77584. [189] Zhao H, Wang ZC, Wang KF, Chen XY. Abeta peptide secretion is reduced by Radix Polygalaeinduced autophagy via activation of the AMPK/mTOR pathway. Mol Med Rep 2015;12(2):27716. [190] Zhang ZH, Wu QY, Zheng R, Chen C, Chen Y, Liu Q, et al. Selenomethionine mitigates cognitive decline by targeting both tau hyperphosphorylation and autophagic clearance in an Alzheimer’s disease mouse model. J Neurosci 2017;37(9):244962. [191] Peixoto CA, de Oliveira WH, da Rocha Araujo SM, Nunes AKS. AMPK activation: Role in the signaling pathways of neuroinflammation and neurodegeneration. Exp Neurol 2017;298(PtA):3141. [192] Lin CL, Huang WN, Li HH, Huang CN, Hsieh S, Lai C, et al. Hydrogen-rich water attenuates amyloid beta-induced cytotoxicity through upregulation of Sirt1-FoxO3a by stimulation of AMP-activated protein kinase in SK-N-MC cells. Chem Biol Interact 2015;240:1221.

I. Sirtuins and metabolic disease

References

19

[193] Kalender A, Selvaraj A, Kim SY, Gulati P, Brule S, Viollet B, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010;11(5):390401. [194] He C, Zhu H, Li H, Zou MH, Xie Z. Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes 2013;62(4):127081. [195] Oda SS. Metformin protects against experimental acrylamide neuropathy in rats. Drug Dev Res 2017;78(7):34959. [196] Zimmerman MA, Biggers CD, Li PA. Rapamycin treatment increases hippocampal cell viability in an mTOR-independent manner during exposure to hypoxia mimetic, cobalt chloride. BMC Neurosci 2018;19(1):82. [197] Liu Z, Stanojevic V, Brindamour LJ, Habener JF. GLP1-derived nonapeptide GLP1(28-36)amide protects pancreatic beta-cells from glucolipotoxicity. J Endocrinol 2012;213(2):14354. [198] He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature. 2012;481(7382):51115. [199] Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition. Autophagy 2016;12(1):1222. [200] Weikel KA, Cacicedo JM, Ruderman NB, Ido Y. Knockdown of GSK3beta increases basal autophagy and AMPK signaling in nutrientladen human aortic endothelial cells. Biosci Rep 2016;36(5): pii e00382. [201] Dong Y, Chen H, Gao J, Liu Y, Li J, Wang J. Molecular machinery and interplay of apoptosis and autophagy in coronary heart disease. J Mol Cell Cardiol 2019;136:2741. [202] An T, Zhang X, Li H, Dou L, Huang X, Man Y, et al. GPR120 facilitates cholesterol efflux in macrophages through activation of AMPK signaling pathway. FEBS J 2020. Available from: https://doi.org/10.1111/febs.15310. [203] Shokri Afra H, Zangooei M, Meshkani R, Ghahremani MH, Ilbeigi D, Khedri A, et al. Hesperetin is a potent bioactivator that activates SIRT1-AMPK signaling pathway in HepG2 cells. J Physiol Biochem 2019;75(2):12533. [204] Qi X, Mitter SK, Yan Y, Busik JV, Grant MB, Boulton ME. Diurnal rhythmicity of autophagy is impaired in the diabetic retina. Cells 2020;9(4):905. [205] Hu P, Lai D, Lu P, Gao J, He H. ERK and Akt signaling pathways are involved in advanced glycation end product-induced autophagy in rat vascular smooth muscle cells. Int J Mol Med 2012;29(4):61318. [206] Lee Y, Hong Y, Lee SR, Chang KT. Autophagy contributes to retardation of cardiac growth in diabetic rats. Lab Anim Res 2012; 28(2):99107. [207] Martino L, Masini M, Novelli M, Beffy P, Bugliani M, Marselli L, et al. Palmitate activates autophagy in INS-1E beta-cells and in isolated rat and human pancreatic islets. PLoS One 2012;7(5):e36188. [208] Kim KA, Shin YJ, Akram M, Kim ES, Choi KW, Suh H, et al. High glucose condition induces autophagy in endothelial progenitor cells contributing to angiogenic impairment. Biol Pharm Bull 2014;37(7):124852. [209] Wang L, Wu W, Chen J, Li Y, Xu M, Cai Y. miR122 and miR199 synergistically promote autophagy in oral lichen planus by targeting the Akt/mTOR pathway. Int J Mol Med 2019;43(3):137381. [210] Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 2008;283(41):2762835. [211] Canto C. Auwerx J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab 2009;20(7):32531. [212] Fulco M, Cen Y, Zhao P, Hoffman EP, McBurney MW, Sauve AA, et al. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell 2008;14(5):66173. [213] Herranz D, Serrano M. SIRT1: recent lessons from mouse models. Nat Rev Cancer 2010;10(12):81923. [214] Paiva MA, Rutter-Locher Z, Goncalves LM, Providencia LA, Davidson SM, Yellon DM, et al. Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury. Am J Physiol Heart Circ Physiol 2011;300(6):H212334. [215] Maiese K. Stem cell guidance through the mechanistic target of rapamycin. World J Stem Cells 2015;7(7):9991009. [216] Maiese K. MicroRNAs and SIRT1: a strategy for stem cell renewal and clinical development? J Transl Sci 2015;1(3):557. [217] Wang N, Luo Z, Jin M, Sheng W, Wang HT, Long X, et al. Exploration of age-related mitochondrial dysfunction and the anti-aging effects of resveratrol in zebrafish retina. Aging (Albany NY) 2019;11(10):311737. [218] Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci 2020;10:54. [219] Dorvash M, Farahmandnia M, Tavassoly I. A systems biology roadmap to decode mTOR control system in cancer. Interdiscip Sci 2020;12(1):111. [220] Maiese K. Molecules to medicine with mTOR: translating critical pathways into novel therapeutic strategies. Elsevier and Academic Press; 2016. ISBN 9780128027332. [221] Maiese K, Chong ZZ, Shang YC, Wang S. mTOR: on target for novel therapeutic strategies in the nervous system. Trends Mol Med 2013;19(1):5160. [222] Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991; 253(5022):9059. [223] Hwang SK, Kim HH. The functions of mTOR in ischemic diseases. BMB Rep 2011;44(8):50611. [224] Maiese K. Erythropoietin and mTOR: a “One-Two Punch” for aging-related disorders accompanied by enhanced life expectancy. Curr Neurovasc Res 2016;13(4):32940. [225] Martinez de Morentin PB, Martinez-Sanchez N, Roa J, Ferno J, Nogueiras R, Tena-Sempere M, et al. Hypothalamic mTOR: the rookie energy sensor. Curr Mol Med 2014;14(1):321. [226] Foster KG, Acosta-Jaquez HA, Romeo Y, Ekim B, Soliman GA, Carriere A, et al. Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation. J Biol Chem 2010;285(1):8094. [227] Wang L, Lawrence Jr. JC, Sturgill TW, Harris TE. Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. J Biol Chem 2009;284(22):146937.

I. Sirtuins and metabolic disease

20

1. Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

[228] Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):87386. [229] Maiese K. Driving neural regeneration through the mammalian target of rapamycin. Neural Regen Res 2014;9(15):141317. [230] Malla R, Ashby Jr. CR, Narayanan NK, Narayanan B, Faridi JS, Tiwari AK. Proline-rich AKT substrate of 40-kDa (PRAS40) in the pathophysiology of cancer. Biochem Biophys Res Commun 2015;463(3):1616. [231] Chong ZZ, Shang YC, Wang S, Maiese K. PRAS40 is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection. PLoS One 2012;7(9):e45456. [232] Shang YC, Chong ZZ, Wang S, Maiese K. WNT1 inducible signaling pathway protein 1 (WISP1) targets PRAS40 to govern beta-amyloid apoptotic injury of microglia. Curr Neurovasc Res 2012;9(4):23949. [233] Wang H, Zhang Q, Wen Q, Zheng Y, Philip L, Jiang H, et al. Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway. Cell Signal 2012;24(1):1724. [234] Xiong X, Xie R, Zhang H, Gu L, Xie W, Cheng M, et al. PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways. Neurobiol Dis 2014;66:4352. [235] Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, et al. GbetaL, a positive regulator of the rapamycinsensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003;11(4):895904. [236] Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 2006;11(6):85971. [237] Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6(11):11228. [238] Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008;416(3):37585. [239] Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR. Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem J 2011;436(1):16979. [240] Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006;16(18):186570. [241] Chong ZZ, Maiese K. Mammalian target of rapamycin signaling in diabetic cardiovascular disease. Cardiovasc Diabetol 2012;11(1):45. [242] Crespo MC, Tome-Carneiro J, Pintado C, Davalos A, Visioli F, Burgos-Ramos E. Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer’s disease. BioFactors (Oxford, England) 2017;43(4). [243] Gu HF, Li N, Tang YL, Yan CQ, Shi Z, Yi SN, et al. Nicotinate-curcumin ameliorates cognitive impairment in diabetic rats by rescuing autophagic flux in CA1 hippocampus. CNS Neurosci Ther 2019;25(4):43041. [244] Maiese K, Chong ZZ, Wang S, Shang YC. Oxidant stress and signal transduction in the nervous system with the PI 3-K, Akt, and mTOR cascade. International J Mol Sci 2013;13(11):1383066. [245] Park JA, Lee CH. Temporal changes in mammalian target of rapamycin (mTOR) and phosphorylated-mTOR expressions in the hippocampal CA1 region of rat with vascular dementia. J Veterinary Sci 2017;18(1):1116. [246] Wang H, Li Q, Sun S, Chen S. Neuroprotective effects of salidroside in a mouse model of Alzheimer’s disease. Cell Mol Neurobiol 2020;40(7):113342. [247] Shang N, Zhang P, Wang S, Chen J, Fan R, Chen J, et al. Aluminum-induced cognitive impairment and PI3K/Akt/mTOR signaling pathway involvement in occupational aluminum workers. Neurotox Res 2020. [248] Cheng J, North BJ, Zhang T, Dai X, Tao K, Guo J, et al. The emerging roles of protein homeostasis-governing pathways in Alzheimer’s disease. Aging Cell 2018;17(5):e12801. [249] Shang YC, Chong ZZ, Wang S, Maiese K. Prevention of beta-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL. Aging (Albany NY) 2012;4(3):187201. [250] Beker MC, Caglayan B, Yalcin E, Caglayan AB, Turkseven S, Gurel B, et al. Time-of-day dependent neuronal injury after ischemic stroke: implication of circadian clock transcriptional factor Bmal1 and survival kinase AKT. Mol Neurobiol 2018;55(3):256576. [251] Ramanathan C, Kathale ND, Liu D, Lee C, Freeman DA, Hogenesch JB, et al. mTOR signaling regulates central and peripheral circadian clock function. PLoS Genet 2018;14(5):e1007369. [252] Angelousi A, Kassi E, Ansari-Nasiri N, Randeva H, Kaltsas G, Chrousos G. Clock genes and cancer development in particular in endocrine tissues. Endocrine-Related Cancer 2019;26(6):R305r17. [253] Sataranatarajan K, Ikeno Y, Bokov A, Feliers D, Yalamanchili H, Lee HJ, et al. Rapamycin increases mortality in db/db mice, a mouse model of type 2 diabetes. J Gerontol A Biol Sci Med Sci 2016;71(7):8507. [254] Fraenkel M, Ketzinel-Gilad M, Ariav Y, Pappo O, Karaca M, Castel J, et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008;57(4):94557. [255] Deblon N, Bourgoin L, Veyrat-Durebex C, Peyrou M, Vinciguerra M, Caillon A, et al. Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats. Br J Pharmacol 2012;165(7):232540. [256] Pasini E, Flati V, Paiardi S, Rizzoni D, Porteri E, Aquilani R, et al. Intracellular molecular effects of insulin resistance in patients with metabolic syndrome. Cardiovasc Diabetol 2010;9:46. [257] Hamada S, Hara K, Hamada T, Yasuda H, Moriyama H, Nakayama R, et al. Upregulation of the mammalian target of rapamycin complex 1 pathway by Ras homolog enriched in brain in pancreatic beta-cells leads to increased beta-cell mass and prevention of hyperglycemia. Diabetes 2009;58(6):132132. [258] Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, et al. Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 2000;408(6815):9947. [259] Zhou J, Wu J, Zheng F, Jin M, Li H. Glucagon-like peptide-1 analog-mediated protection against cholesterol-induced apoptosis via mammalian target of rapamycin activation in pancreatic betaTC-6 cells -1mTORbetaTC-6. J Diabetes 2015;7(2):2319. [260] Liu YW, Zhang L, Li Y, Cheng YQ, Zhu X, Zhang F, et al. Activation of mTOR signaling mediates the increased expression of AChE in high glucose condition: in vitro and in vivo evidences. Mol Neurobiol 2016;53(7):497280.

I. Sirtuins and metabolic disease

References

21

[261] Miao XY, Gu ZY, Liu P, Hu Y, Li L, Gong YP, et al. The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic betacell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway. Peptides 2013;39:719. [262] Jung CH, Lee DH, Ahn J, Lee H, Choi WH, Jang YJ, et al. γ-Oryzanol enhances adipocyte differentiation and glucose uptake. Nutrients 2015;7(6):485161. [263] Malla R, Wang Y, Chan WK, Tiwari AK, Faridi JS. Genetic ablation of PRAS40 improves glucose homeostasis via linking the AKT and mTOR pathways. Biochem Pharmacol 2015. [264] Chen C, Xu Y, Song Y. IGF-1 gene-modified muscle-derived stem cells are resistant to oxidative stress via enhanced activation of IGF1R/PI3K/AKT signaling and secretion of VEGF. Mol Cell Biochem 2014;386(1-2):16775. [265] Nagel G, Peter RS, Rosenbohm A, Koenig W, Dupuis L, Rothenbacher D, et al. Association of insulin-like growth factor 1 concentrations with risk for and prognosis of amyotrophic lateral sclerosis - results from the ALS registry Swabia. Sci Rep 2020;10(1):736. [266] Huang D, Shen S, Cai M, Jin L, Lu J, Xu K, et al. Role of mTOR complex in IGF-1 induced neural differentiation of DPSCs. J Mol Histol 2019;. [267] Xie T, Ye W, Liu J, Zhou L, Song Y. The emerging key role of klotho in the hypothalamus-pituitary-ovarian axis. Reprod Sci 2020. [268] Maiese K, Chong ZZ, Shang YC. Raves and risks for erythropoietin. Cytokine Growth Factor Rev 2008;19(2):14555. [269] Maiese K, Hou J, Chong ZZ, Shang YC. A fork in the path: developing therapeutic inroads with FoxO proteins. Oxid Med Cell Longev 2009;2(3):11929. [270] Montesano A, Bonfigli AR, De Luca M, Crocco P, Garagnani P, Marasco E, et al. Erythropoietin (EPO) haplotype associated with allcause mortality in a cohort of Italian patients with Type-2 Diabetes. Sci Rep 2019;9(1):10395. [271] Maiese K, Chong ZZ, Hou J, Shang YC. Oxidative stress: biomarkers and novel therapeutic pathways. Exp Gerontol 2010;45(3):21734. [272] Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. Jama. 2005;293(1):905. [273] Lee HJ, Koh SH, Song KM, Seol IJ, Park HK. The Akt/mTOR/p70S6K pathway is involved in the neuroprotective effect of erythropoietin on hypoxic/ischemic brain injury in a neonatal rat model. Neonatology 2016;110(2):93100. [274] Maiese K, Chong ZZ, Shang YC, Wang S. Erythropoietin: new directions for the nervous system. Int J Mol Sci 2012;13(9):1110229. [275] Wang GB, Ni YL, Zhou XP, Zhang WF. The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis. Mol Cell Biochem 2014;385(1-2):12532. [276] Esmaeili Tazangi P, Moosavi SM, Shabani M, Haghani M. Erythropoietin improves synaptic plasticity and memory deficits by decrease of the neurotransmitter release probability in the rat model of Alzheimer’s disease. Pharmacol Biochem Behav 2015;130:1521. [277] Li YP, Yang GJ, Jin L, Yang HM, Chen J, Chai GS, et al. Erythropoietin attenuates Alzheimer-like memory impairments and pathological changes induced by amyloid beta42 in mice. Brain Res 2015;1618:15967. [278] Sun J, Martin JM, Vanderpoel V, Sumbria RK. The promises and challenges of erythropoietin for treatment of Alzheimer’s disease. Neuromolecular Med 2019;21(1):1224. [279] Maiese K. Preserving brain function during development and aging with erythropoietin. Curr Neurovasc Res 2019;16(4):28990. [280] Chong ZZ, Hou J, Shang YC, Wang S, Maiese K. EPO relies upon novel signaling of Wnt1 that requires Akt1, FoxO3a, GSK-3beta, and beta-Catenin to foster vascular integrity during experimental diabetes. Curr Neurovasc Res 2011;8(2):10320. [281] Chong ZZ, Shang YC, Maiese K. Vascular injury during elevated glucose can be mitigated by erythropoietin and Wnt signaling. Curr Neurovasc Res 2007;4(3):194204. [282] Gradinaru D, Margina D, Ilie M, Borsa C, Ionescu C, Prada GI. Correlation between erythropoietin serum levels and erythrocyte susceptibility to lipid peroxidation in elderly with type 2 diabetes. Acta Physiol Hung 2015;102(4):4008. [283] Hamed S, Bennett CL, Demiot C, Ullmann Y, Teot L. Desmouliere A. Erythropoietin, a novel repurposed drug: an innovative treatment for wound healing in patients with diabetes mellitus. Wound Repair Regen: Official Publication of the Wound Healing Society [and] the European Tissue Repair Society 2014;22(1):2333. [284] Niu HS, Chang CH, Niu CS, Cheng JT, Lee KS. Erythropoietin ameliorates hyperglycemia in type 1-like diabetic rats. Drug Des Devel Ther 2016;10:187784. [285] Maiese K. Regeneration in the nervous system with erythropoietin. Front Biosci (Landmark edition) 2016;21:56196. [286] Wang L, Teng R, Di L, Rogers H, Wu H, Kopp JB, et al. PPARalpha and Sirt1 mediate erythropoietin action in increasing metabolic activity and browning of white adipocytes to protect against obesity and metabolic disorders. Diabetes 2013;62(12):412231. [287] Wang L, Jia Y, Rogers H, Wu YP, Huang S, Noguchi CT. GATA-binding protein 4 (GATA-4) and T-cell acute leukemia 1 (TAL1) regulate myogenic differentiation and erythropoietin response via cross-talk with Sirtuin1 (Sirt1). J Biol Chem 2012;287(36):3015769. [288] Wu H, Wang H, Zhang W, Wei X, Zhao J, Yan P, et al. rhEPO affects apoptosis in hippocampus of aging rats by upregulating SIRT1. Int J Clin Exp Pathol 2015;8(6):687080. [289] Guo W, Qian L, Zhang J, Zhang W, Morrison A, Hayes P, et al. Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling. J Neurosci Res 2011;89(11):172336. [290] Zhang S, Cai G, Fu B, Feng Z, Ding R, Bai X, et al. SIRT1 is required for the effects of rapamycin on high glucose-inducing mesangial cells senescence. Mech Ageing Dev 2012;133(6):387400. [291] Kang S, Chemaly ER, Hajjar RJ, Lebeche D. Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. J Biol Chem 2011;286(21):1846573. [292] Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA. Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 2011;60(3):82737. [293] Li F, Chong ZZ, Maiese K. Cell life versus cell longevity: the mysteries surrounding the NAD(1) precursor nicotinamide. Curr Med Chem 2006;13(8):88395. [294] Maiese K, Chong ZZ. Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain. Trends Pharmacol Sci 2003;24 (5):22832. [295] Maiese K, Chong ZZ, Hou J, Shang YC. The vitamin nicotinamide: translating nutrition into clinical care. Molecules. 2009; 14(9):344685.

I. Sirtuins and metabolic disease

22

1. Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

[296] Braidy N, Liu Y. NAD 1 therapy in age-related degenerative disorders: a benefit/risk analysis. Exp Gerontol 2020;110831. [297] Rex A, Fink H. Pharmacokinetic aspects of reduced nicotinamide adenine dinucleotide (NADH) in rats. Front Biosci 2008;13:373541. [298] Li F, Chong ZZ, Maiese K. Navigating novel mechanisms of cellular plasticity with the NAD 1 precursor and nutrient nicotinamide. Front Biosci 2004;9:250020. [299] Jackson TM, Rawling JM, Roebuck BD, Kirkland JB. Large supplements of nicotinic acid and nicotinamide increase tissue NAD 1 and poly(ADP-ribose) levels but do not affect diethylnitrosamine-induced altered hepatic foci in Fischer-344 rats. J Nutr 1995; 125(6):145561. [300] Wojcik M, Seidle HF, Bieganowski P, Brenner C. Glutamine-dependent NAD 1 synthetase. How a two-domain, three-substrate enzyme avoids waste. J Biol Chem 2006;281(44):33395402. [301] Khan JA, Forouhar F, Tao X, Tong L. Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery. Expert Opin Ther Targets 2007;11(5):695705. [302] Khan JA, Xiang S, Tong L. Crystal structure of human nicotinamide riboside kinase. Structure 2007;15(8):100513. [303] Maiese K. Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus. Biomed Pharmacother 2008;62(4):21832. [304] Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S. Enzymology of NAD 1 homeostasis in man. Cell Mol Life Sci 2004;61(1):1934. [305] Lin SJ, Guarente L. Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol 2003;15(2):2416. [306] Hageman GJ, Stierum RH. Niacin, poly(ADP-ribose) polymerase-1 and genomic stability. Mutat Res 2001;475(12):4556. [307] Qi Z, Xia J, Xue X, He Q, Ji L, Ding S. Long-term treatment with nicotinamide induces glucose intolerance and skeletal muscle lipotoxicity in normal chow-fed mice: compared to diet-induced obesity. J Nutr Biochem 2016;36:3141. [308] Shear DA, Dixon CE, Bramlett HM, Mondello S, Dietrich WD, Deng-Bryant Y, et al. Nicotinamide treatment in traumatic brain injury: operation brain trauma therapy. J Neurotrauma 2016;33(6):52337. [309] Kiuchi K, Yoshizawa K, Shikata N, Matsumura M, Tsubura A. Nicotinamide prevents N-methyl-N-nitrosourea-induced photoreceptor cell apoptosis in Sprague-Dawley rats and C57BL mice. Exp Eye Res 2002;74(3):38392. [310] Lin SH, Vincent A, Shaw T, Maynard KI, Maiese K. Prevention of nitric oxide-induced neuronal injury through the modulation of independent pathways of programmed cell death. J Cereb Blood Flow Metab 2000;20(9):138091. [311] Chong ZZ, Lin SH, Maiese K. Nicotinamide modulates mitochondrial membrane potential and cysteine protease activity during cerebral vascular endothelial cell injury. J Vasc Res 2002;39(2):13147. [312] Mahmoud YI, Mahmoud AA. Role of nicotinamide (vitamin B3) in acetaminophen-induced changes in rat liver: nicotinamide effect in acetaminophen-damaged liver. Exp Toxicol Pathol 2016;68(6):34554. [313] Naia L, Rosenstock TR, Oliveira AM, Oliveira-Sousa SI, Caldeira GL, Carmo C, et al. Comparative mitochondrial-based protective effects of resveratrol and nicotinamide in Huntington’s disease models. Mol Neurobiol 2016;54(7):538599. [314] Jayaram HN, Kusumanchi P, Yalowitz JA. NMNAT expression and its relation to NAD metabolism. Curr Med Chem 2011; 18(13):196272. [315] Feng Y, Wang Y, Jiang C, Fang Z, Zhang Z, Lin X, et al. Nicotinamide induces mitochondrial-mediated apoptosis through oxidative stress in human cervical cancer HeLa cells. Life Sci 2017;181:629. [316] Kulkarni CA, Brookes P. Cellular compartmentation and the redox/non-redox functions of NAD1 . Antioxid Redox Signal 2019; 31(9):62342. [317] Ahangarpour A, Ramezani Ali Akbari F, Fathi, Moghadam H. Effect of C-peptide alone or in combination with nicotinamide on glucose and insulin levels in streptozotocin-nicotinamide-induced type 2 diabetic mice. Malaysian J Med Sci: MJMS 2014; 21(4):1217. [318] Folwarczna J, Janas A, Cegiela U, Pytlik M, Sliwinski L, Matejczyk M, et al. Caffeine at a moderate dose did not affect the skeletal system of rats with streptozotocin-induced diabetes. Nutrients 2017;9(11):1196. [319] Ghasemi A, Khalifi S, Jedi S. Streptozotocin-nicotinamide-induced rat model of type 2 diabetes (review). Acta Physiol Hung 2014; 101(4):40820. [320] Guo S, Chen Q, Sun Y, Chen J. Nicotinamide protects against skeletal muscle atrophy in streptozotocin-induced diabetic mice. Arch Physiol Biochem 2019;125(5):4707. [321] Lai YF, Wang L, Liu WY. Nicotinamide pretreatment alleviates mitochondrial stress and protects hypoxic myocardial cells via AMPK pathway. Euro Rev Med Pharmacol Sci 2019;23(4):1797806. [322] Lee HJ, Yang SJ. Supplementation with nicotinamide riboside reduces brain inflammation and improves cognitive function in diabetic mice. Int J Mol Sci 2019;20(17). [323] Reddy S, Bibby NJ, Wu D, Swinney C, Barrow G, Elliott RB. A combined casein-free-nicotinamide diet prevents diabetes in the NOD mouse with minimum insulitis. Diabetes Res Clin Pract 1995;29(2):8392. [324] Hu Y, Wang Y, Wang L, Zhang H, Zhao B, Zhang A, et al. Effects of nicotinamide on prevention and treatment of streptozotocininduced diabetes mellitus in rats. Chin Med J (Engl) 1996;109(11):81922. [325] Chlopicki S, Swies J, Mogielnicki A, Buczko W, Bartus M, Lomnicka M, et al. 1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway. Br J Pharmacol 2007; 152(2):2309. [326] Chong ZZ, Lin SH, Li F, Maiese K. The sirtuin inhibitor nicotinamide enhances neuronal cell survival during acute anoxic injury through Akt, Bad, PARP, and mitochondrial associated “anti-apoptotic” pathways. Curr Neurovasc Res 2005;2(4):27185. [327] Hara N, Yamada K, Shibata T, Osago H, Hashimoto T, Tsuchiya M. Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells. J Biol Chem 2007;282(34):2457482. [328] Ieraci A, Herrera DG. Nicotinamide protects against ethanol-induced apoptotic neurodegeneration in the developing mouse brain. PLoS Med 2006;3(4):e101.

I. Sirtuins and metabolic disease

References

23

[329] Tam D, Tam M, Maynard KI. Nicotinamide modulates energy utilization and improves functional recovery from ischemia in the in vitro rabbit retina. Ann N Y Acad Sci 2005;1053:25868. [330] Olmos PR, Hodgson MI, Maiz A, Manrique M, De Valdes MD, Foncea R, et al. Nicotinamide protected first-phase insulin response (FPIR) and prevented clinical disease in first-degree relatives of type-1 diabetics. Diabetes Res Clin Pract 2006;71(3):32033. [331] Crino A, Schiaffini R, Ciampalini P, Suraci MC, Manfrini S, Visalli N, et al. A two year observational study of nicotinamide and intensive insulin therapy in patients with recent onset type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2005;18(8):74954. [332] Liu HK, Green BD, Flatt PR, McClenaghan NH, McCluskey JT. Effects of long-term exposure to nicotinamide and sodium butyrate on growth, viability, and the function of clonal insulin secreting cells. Endocr Res 2004;30(1):618. [333] Reddy S, Salari-Lak N, Sandler S. Long-term effects of nicotinamide-induced inhibition of poly(adenosine diphosphate-ribose) polymerase activity in rat pancreatic islets exposed to interleukin-1 beta. Endocrinology 1995;136(5):190712. [334] Gaudineau C, Auclair K. Inhibition of human P450 enzymes by nicotinic acid and nicotinamide. Biochem Biophys Res Commun 2004;317(3):9506. [335] Han J, Shi S, Min L, Wu T, Xia W, Ying W. NAD(1) treatment induces delayed autophagy in Neuro2a cells partially by increasing oxidative stress. Neurochem Res 2011;36(12):22707. [336] Kim SW, Lee JH, Moon JH, Nazim UM, Lee YJ, Seol JW, et al. Niacin alleviates TRAIL-mediated colon cancer cell death via autophagy flux activation. Oncotarget. 2016;7(4):435668. [337] Jang SY, Kang HT, Hwang ES. Nicotinamide-induced mitophagy: event mediated by high NAD1/NADH ratio and SIRT1 protein activation. J Biol Chem 2012;287(23):1930414. [338] Shen C, Dou X, Ma Y, Ma W, Li S, Song Z. Nicotinamide protects hepatocytes against palmitate-induced lipotoxicity via SIRT1dependent autophagy induction. Nutr Res 2017;40:407. [339] Audrito V, Vaisitti T, Rossi D, Gottardi D, D’Arena G, Laurenti L, et al. Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Res 2011; 71(13):447383. [340] Zhang JG, Zhao G, Qin Q, Wang B, Liu L, Liu Y, et al. Nicotinamide prohibits proliferation and enhances chemosensitivity of pancreatic cancer cells through deregulating SIRT1 and Ras/Akt pathways. Pancreatology 2013;13(2):1406. [341] Zhang XM, Jing YP, Jia MY, Zhang L. Negative transcriptional regulation of inflammatory genes by group B3 vitamin nicotinamide. Mol Biol Rep 2012;39(12):1036771.

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2 Sirtuins in metabolic and epigenetic regulation of stem cells Yi Fang and Xiaoling Li Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States O U T L I N E 2.1 Introduction

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2.2 Stem cells and sirtuins

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2.3 SIRT1 in stem cell biology 2.3.1 SIRT1 is important for normal embryogenesis and animal development 2.3.2 SIRT1 maintains pluripotent ESCs through multilevel mechanisms 2.3.3 SIRT1 is important for the maintenance of diverse ASC pools 2.3.4 SIRT1 is important in maintaining/promoting stemness and survival of CSCs

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2.4 SIRT2 in stem cell biology 2.4.1 SIRT2 promotes differentiation of ESCs in vitro 2.4.2 SIRT2 promotes survival of CSCs

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2.5 SIRT3 in stem cell biology

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2.5.1 SIRT3 maintains the pool and regenerative capacity of HSCs during aging

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2.6 SIRT6 in stem cell biology 32 2.6.1 SIRT6 epigenetically promotes proper lineage commitment of ESCs and animal development 32 2.6.2 SIRT6 controls regeneration and stress resistance in HSCs and mesenchymal stem cells 33 2.6.3 SIRT6 suppresses stemness of CSCs 33

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2.7 SIRT7 in stem cell biology 2.7.1 SIRT7 regulates embryogenesis and life span through maintenance of genome stability 2.7.2 SIRT7 regulates quiescence and regenerative capacity of HSCs

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2.8 Concluding remarks and future perspectives

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References

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2.1 Introduction Sirtuins are highly conserved NAD1-dependent protein deacylases, which function to transfer a variety of lipid acyl-groups, including acetyl, succinyl, malonyl, glutaryl, or long-chain acyl-groups, from the substrate proteins to the adenosine diphosphate ribose (ADP)-ribose moiety of NAD1 [14]. Seven members of sirtuins have been identified in mammals (SIRT1 to SIRT7) [5], and these seven proteins are localized in distinct subcellular localizations and have different tissue expression patterns with differential substrate specificities [610]. Since NAD1 is required for sirtuins’ enzymatic activity and the concentration of NAD1 is determined by cellular metabolic state, sirtuins are able to sense cellular energy status and then modulate the functions of a wide array of protein substrates, ranging from histones and transcription factors to metabolic enzymes and cell membrane proteins. Consistently, a wealth of studies demonstrate that sirtuins play critical roles in modulating metabolism homeostasis, nutrient sensing, aging, and age-associated conditions/diseases [11,12]. Sirtuin Biology in Cancer and Metabolic Disease. DOI: https://doi.org/10.1016/B978-0-12-822467-0.00004-8

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© 2021 Elsevier Inc. All rights reserved.

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Emerging evidence has revealed that members of the Sirtuin family of unique enzymes also function as pivotal regulators of stem cell biology. Stem cells, including pluripotent stem cells (PSCs) and adult stem cells (ASCs), are characterized by their ability to self-renew while maintaining their pluri/multipotency. This ability is supported by unique sets of metabolism programs and specific epigenetic status in stem cells. For instance, the rapidly proliferating embryonic stem cells (ESCs) demand a high glycolytic flux under aerobic conditions (“Warburg effect”), and are also dependent on exogenous glutamine and one-carbon catabolism [1319]. These metabolic programs not only provide anabolic precursors for rapid cell proliferation, but also produce many intermediate metabolites, including acetyl-CoA, NAD1, α-ketoglutarate, and S-adenosylmethionine (SAM), which function as substrates or cofactors for enzymes that regulate chromatin modification and gene expression [1924]. Thus the unique metabolic state of stem cells directly links to distinctive epigenetics and gene expression profiles, greatly influencing their self-renewal and pluri-/multipotency [15,25]. Recent literature shows that sirtuins are important in maintaining stem cell pluri-/multipotency, promoting cell survival, and regulating differentiation by modulating metabolisms and epigenetics. In this chapter, we summarize the involvement of individual sirtuins in metabolic and epigenetic regulation of stem cells, including PSCs and embryogenesis, ASCs and tissue regeneration, as well as cancer stem cells (CSCs) and cancers.

2.2 Stem cells and sirtuins PSCs are stem cells that give rise to all cells involved in tissue development in the body. There are two types of PSCs, ESCs and induced pluripotent stem cells (iPSCs). ESCs are derived from the inner cell mass (ICM) of preimplantation embryos. iPSCs are reprogrammed from adult somatic cells in vitro through simultaneous overexpression of four core pluripotent factors, Oct4, Sox2, Klf4, and cMyc (OSKM). Both ESCs and iPSCs can be indefinitely maintained and expanded in the pluripotent state in vitro, and are capable of differentiating into all the derivatives of the three germ layers. Among the seven sirtuin members, SIRT1 has the highest expression in mouse ESCs (mESCs), followed by SIRT6 and SIRT7, while the expression of other sirtuins, including mitochondrial sirtuins, is low in mESCs [26]. Furthermore, germline knocking out SIRT1, SIRT6, or SIRT7, but not other sirtuins, causes significant developmental defects [7,2733], demonstrating that those three nuclear sirtuins are important in the regulation of ESC biology and animal development. ASCs are stem cells that persist throughout the life to replace cells lost due to homeostatic turnover, disease, and injury [34,35]. They are characterized by their ability to self-renew and differentiate to generate all the cell types in a tissue. ASC populations have varying proliferative plasticity and distinct turnover patterns in different tissues. Based on their turnover rates in various tissues/organs, ASCs can be categorized into three types: ASCs that continuously cycle themselves in high-turnover tissues, like intestinal stem cells (ISCs) and the short-term hematopoietic stem cells (ST-HSCs); ASCs that are maintained in quiescent state, and whose proliferation is strongly induced by injury or other environmental/developmental cues, such as muscle satellite cells (SCs), adult neural stem cells (NSCs), and long-term hematopoietic stem cells (LT-HSCs); and ASCs that periodically alternate between quiescent and proliferative states, like hair follicle stem cells. In a given tissue, ASCs are all delicately balanced between quiescence, proliferation/self-renewal, and differentiation. Disruption of ASC homeostasis, either by a decline in ASC number and/or functions or by aberrant activation of ASCs, has been linked to a number of human disorders, including degenerative disease, aging, and cancer. Recent evidence indicates that sirtuins, including SIRT1, SIRT3, SIRT6, and SIRT7 are critical in maintaining ASC (particularly HSC) homeostasis, tissue regeneration, and aging through diverse mechanisms. CSCs, similar to normal stem cells, possess the ability to self-renew and differentiate to give rise to all the cell types in a cancer [36]. Although they are a small population of a tumor, CSCs are able to generate a new tumor, resulting in tumor relapse and metastasis [37,38]. As conventional chemotherapy and radiotherapy designed to reduce cancer mass primarily target the differentiated or differentiating cancer cells but fail to kill CSCs, development of therapy against CSCs would greatly improve the survival and life quality of certain cancer patients, particularly for patients with metastatic tumors. Given the importance of sirtuins in PSCs and ASCs, it is not surprising that several members of this family, including SIRT1, SIRT2, and SIRT6, are also key regulators of CSC functions [39].

2.3 SIRT1 in stem cell biology 2.3.1 SIRT1 is important for normal embryogenesis and animal development SIRT1 is highly expressed in preimplantation embryos, ESCs, and male germ cells, but has relatively low expression in differentiated cells and tissues, as well as most adult tissues [27,40,41]. This tissue expression

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pattern suggests a fundamentally important role of SIRT1 in ESCs, embryogenesis and development. In particular, SIRT1 is most highly expressed at the 2-cell stage when the embryos begin to activate its own genome [41], implying that SIRT1 is one of the first activated genes during embryogenesis. Consistently, SIRT1 null zygotes generated through in vitro fertilization of SIRT1 deficient sperm and oocytes display a substantially compromised efficiency of developing to the two-cell stage compared to control zygotes [42]. Importantly, germline deletion of SIRT1 in mice results in severe developmental defects on various genetic backgrounds, including intrauterine growth retardation, developmental defects of the retina and heart, defective germ cell differentiation, bone developmental delay, and neonatal lethality [27,28,4345]. Additionally, impaired SIRT1 stability induced by loss of USP22, a deubiquitinating enzyme that stabilizes SIRT1, is also linked to defective embryogenesis in USP22 deficiency mice [46]. Please note that depending on different genetic backgrounds, there are some variations in the penetrance and severity of SIRT1 deletion-induced developmental phenotypes. Mice lacking SIRT1 on the FVB/N genetic background [47] or a few percentages of SIRT1 null mice on some mixed backgrounds [27,28] can survive into adulthood. However, despite these variations, growth retardation and sterility with developmental defects are all observed in these adult mice. Specifically, spermatogenic stem cell number in E15.5 embryos is severely reduced, and spermatogenesis but not oogenesis is abrogated in adult SIRT1 knockout animals [42]. Moreover, germ cell-specific deletion of SIRT1 still disrupts spermatogenesis, indicating that the action of SIRT1 in germ cells is cell-autonomous [44,48]. All these observations strongly indicate that SIRT1 is a key regulator of normal embryogenesis and animal development.

2.3.2 SIRT1 maintains pluripotent ESCs through multilevel mechanisms SIRT1 deficiency leads to loss of pluripotency and reduced survival of ESCs. Consistent with its high expression in ESCs, SIRT1 maintains pluripotency by interacting with key pluripotency genes, such as Oct4 and Myc, modulating DNA methylation, and meanwhile repressing differentiation signals such as cellular retinoic acid (RA) signaling. SIRT1 also promotes ESC survival by regulating cellular endogenous reactive oxygen species (ROS) responses and suppressing p53 activation-induced DNA damage and apoptosis. So SIRT1 is multifaceted in pluripotency maintenance (Fig. 2.1). In hESCs, SIRT1 is one of the downstream factors mediating Oct4-dependent pluripotency maintenance [49]. Oct4 transcriptionally activates the expression of SIRT1, which in turn deacetylates and destabilizes p53, a well-known SIRT1 deacetylation substrate [49], to promote pluripotency. Consistently, silencing Oct4 leads to a reduction of SIRT1 expression and activation of p53, which induces hESC differentiation [49]. In mESCs, SIRT1 maintains the naı¨ve state through direct deacetylation of Oct4 [50]. During the naive-to-primed transition, the activity of SIRT1 is reduced and Oct4 becomes hyperacetylated. Acetylated Oct4 binds to an enhancer to induce the expression of Otx2, which interacts with acetylated Oct4 to induce the primed pluripotency gene network [50]. In addition to Oct4, SIRT1 also deacetylates Myc to metabolically and epigenetically maintain pluripotent mESCs [41]. Deacetylation of Myc, including both N-Myc and c-Myc, stabilizes Myc and/or enhances its recruitment to a promoter of methionine adenosyltransferase 2a (Mat2a), thereby promoting Mat2a expression. Mat2a is critical to the conversion of methionine to SAM and the maintenance of appropriate methylation levels of FIGURE 2.1 SIRT1 is a multifaceted regulator

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in the pluripotent ESCs. SIRT1 is critically involved in the maintenance of pluripotent ESCs and animal development through multilevel mechanisms. The expression of SIRT1 in ESCs is under transcriptional control of Oct4, and the interaction between SIRT1, Oct4, and Myc are important to metabolically and epigenetically maintain pluripotent ESCs. SIRT1 also actively represses the expression of developmental and differentiation genes through deacetylation of histones and inhibition of cellular RA signaling. Finally, SIRT1 enhances stress response of ESCs by repressing p53 and promoting DNA repair.

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histones, especially H3K4me3. Therefore deletion of SIRT1 reduces Mat2a expression and H3K4me3 level, altering gene expression profiles, compromising the pluripotency, and sensitizing mESCs to methionine restriction-induced differentiation and apoptosis [41]. This SIRT1-Myc regulated metabolic and epigenetic regulation is also important to animal development, as SIRT1 KO embryos are sensitive to maternal methionine restriction-induced lethality, whereas maternal methionine supplementation increases the survival of SIRT1 KO newborn mice [41]. SIRT1 also actively maintains pluripotency by selectively preventing abnormal DNA methylation of some developmental genes in mESCs through antagonizing Dnmt3l [51]. Dnmt3l is a catalytically inactive DNA methyltransferase that interacts with Dnmt3a and Dnmt3b to stimulate de novo methylation [5254]. SIRT1 transcriptionally suppresses Dnmt3l expression and physically deacetylates Dnmt3l, thereby destabilizing Dnmt3l protein [51]. SIRT1 deficiency leads to a high level of Dnmt3l, abnormal DNA methylation, repressed expression of imprinted and germline genes, and delayed neurogenesis and spermatogenesis [51]. Therefore, SIRT1-mediated DNA methylation status is important for the maintenance of differentiation potential or pluripotency in ESCs. Additionally, SIRT1 directly represses differentiation of ESCs by regulating histone acetylation and RA signaling. Highly expressed SIRT1 in ESCs deacetylates histones and represses the transcription of some developmental genes, while reduction of SIRT1 during differentiation reactivates expression of these key developmental genes [55]. During differentiation, SIRT1 level is reduced either by microRNAs-mediated inhibition of SIRT1 protein translation [40], or by CARM1-HuR-dependent destabilization of SIRT1 mRNA [55,56]. SIRT1 also represses the differentiation of mESCs through inhibiting RA signaling [45]. CRABPII, a cellular RA binding protein that is translocated into the nucleus to activate retinoic acid receptor (RAR) signaling upon RA treatment, becomes acetylated in the nucleus. SIRT1 interacts with and deacetylates CRABPII, recycling CRABPII back to the cytosol, thereby inactivating the RAR-mediated activation of differentiation genes. Notably, SIRT1 deficiency-induced development defects in mice, particularly bone development delay, are associated with increased RA signaling [45]. Finally, SIRT1 is important in regulating ESC survival in response to various stresses. SIRT1 strongly enhances the survival of hESCs by promoting DNA repair and inhibiting p53 [57], and promotes telomere elongation and genome stability during reprogramming in iPSCs [58]. SIRT1 also protects ESCs against different degrees of oxidative stress via different mechanisms. In response to endogenous ROS, SIRT1 functions to maintain heathy pluripotent ESCs by sensitizing mESCs to mitochondrial p53-induced apoptosis while inhibiting nuclear p53-mediated suppression of Nanog expression [59]. In contrast, SIRT1 protects ESCs from apoptosis induced by high concentrations of exogenous ROS (e.g., 1 mM H2O2) in part through the class III PI3K/Beclin 1 and mTOR-mediated autophagy [60]. Collectively, SIRT1 is critically involved in the maintenance of pluripotent ESCs and animal development through regulation of pluripotency factors, metabolism, epigenetics, redox homeostasis, and cellular stress response.

2.3.3 SIRT1 is important for the maintenance of diverse ASC pools SIRT1 is an important factor for preserving ASC pools in multiple tissues through diverse mechanisms (Fig. 2.2). SIRT1 interacts with Lamin A protein to prevent progeroid syndrome, a group of rare genetic disorders characterized with severe early-onset premature aging [61]. Progeroid syndrome is caused by progerin, a truncated Lamin A protein in human. Knockout of Zmpste24, a metalloproteinase responsible for prelamin A maturation, recapitulates the phenotypes of progerin, and results in quick depletion of multiple ASC pools including mesenchymal stem cells (MSCs), hair follicle progenitor cells, and hematopoietic stem cells (HSCs) in mice [61]. Liu et al showed that both progerin and unprocessed prelamin A protein are defective in binding and activation of SIRT1, while promoting interaction between SIRT1 and Lamin A by resveratrol activates SIRT1 and rescues ASC decline in Zmpste242/2 mice [61]. In addition, long-term culture with resveratrol retains MSCs’ proliferative and differentiation potential, and resveratrol treatment significantly improves bone regeneration after MSC transplantation in rats [62]. These findings indicate that maintaining ASC pools could be one of the mechanisms through which SIRT1 promotes longevity. In ASCs that continuously divide asymmetrically in high-turnover tissues, such as ISCs, SIRT1 is necessary and sufficient to promote their self-renewal and expansion in response to caloric restriction (CR) [63]. CR activates SIRT1 in ISCs, which then deacetylates S6K1, facilitating mTORC1 to phosphorylate S6K1 and stimulating protein synthesis [63]. To activate SIRT1, CR promotes production of a paracrine factor cyclic ADP ribose (cADPR) in Paneth cells, a key constituent of the mammalian ISC niche, but not in ISCs [64]. The released cADPR

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FIGURE 2.2

SIRT1 is important for the maintenance of diverse ASC pools. SIRT1 is critical to maintain diverse ASC pools through maintenance of self-renewal or quiescence and regeneration capacity, particularly in response to environmental stress and injury. In the intestine, caloric restriction promotes production of cADPR in Paneth cells, which function in ISCs to promote NAD1 synthesis and SIRT1 activity. Activated SIRT1 then deacetylates S6K1, promoting its phosphorylation by mTORC1 and subsequent protein synthesis. This action of SIRT1 is important for ISCs self-renewal. In muscle stem cells SCs, SIRT1 represses muscle specific gene expression to maintain their quiescence and regeneration capacity. Injury induces a metabolic switch from oxidative phosphorylation to glycolysis, which reduces cellular NAD1 levels and SIRT1 activity, leading to desuppression of muscle genes and SC differentiation. In HSCs, SIRT1 represses the activity of p53 and transcription of Hox9 to maintain their genome stability and proliferation in response to environmental stress.

then acts on ISCs to activate CaMKK and AMPK, thereby stimulating the transcription of Nampt, the ratelimiting enzyme in a NAD1 salvage pathway, and enhancing the activity of SIRT1 [63,64]. This data also suggests that SIRT1-mediated preservation of the ASC pool could be a part of the longevity response to CR. In ASCs that are maintained in quiescent state but strongly induced by injury, such as the skeletal muscle stem cells SCs and adult NSCs, SIRT1 is required for the maintenance of their quiescence and regeneration capacity [6567]. When quiescent SCs are induced to proliferate upon injury, SIRT1 activity is decreased by reduced intracellular NAD1 levels due to a metabolic switch from fatty acid oxidation to glycolysis [65]. As a result, H4K16ac level is elevated, and muscle gene transcription is enhanced [65]. When the deacetylase domain of SIRT1 is specifically ablated in skeletal muscle, myogenic genes are expressed in SCs, leading to premature differentiation, and impairing muscle growth during development and regeneration upon injury [65]. In adult NSCs, SIRT1 also maintains their quiescence, as specific deletion of SIRT1 in adult NSCs enhances their self-renewal [66,67] and promotes lineage specification to oligodendrocyte progenitor cells/oligodendrocytes [68]. This impact of SIRT1 is also sensitive to metabolic switch/redox stress and involves inhibition of Hes1 transcription factor [66], Notch signaling [67], or cell metabolism and growth factor signaling [68]. It would be interesting to determine whether SIRT1 similarly impacts long-term maintenance of the NSC pool and neurogenesis in response to injury as in SCs and skeletal muscle in the future. SIRT1 is also important for the maintenance of quiescence and regeneration capacity of HSCs in response to environmental stress and aging [69]. SIRT1 KO mice do not exhibit any abnormalities in their hematopoietic compartment under normal conditions [70]. However, SIRT1 deficient mESCs are compromised in their hematopoietic commitment in vitro and SIRT1 KO mice have decreased survival of hematopoietic progenitors ex vivo, particularly under hypoxic conditions or under conditions of delayed growth factor addition [71]. Moreover,

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conditional ablation of SIRT1 in adult hematopoietic stem/progenitor cells (HSPCs) cell-autonomously induces HSPC expansion and loss of long-term repopulation capacity under stress [72]. This stress-induced loss of HSC function is associated with genomic instability, p53 activation, and increased DNA damage in SIRT1-deficient HSPCs [72]. SIRT1 loss also causes a significant increase of H4K16ac and upregulates the expression of Hoxa9, a key regulator of HSPC function and proliferation [72]. Collectively, SIRT1 is critical to maintain diverse ASC pools through maintenance of self-renewal or quiescence and regeneration capacity, particularly in response to stress and injury (Fig. 2.2).

2.3.4 SIRT1 is important in maintaining/promoting stemness and survival of CSCs Consistent with its role in maintenance of pluripotent ESCs and functional pools of ASCs, SIRT1 is critical for stemness and survival of CSCs (Fig. 2.3). For example, SIRT1 is highly expressed in a number of CSCs, such as glioma stem cells (GSCs), breast cancer stem cells (BCSCs), colorectal CSC-like cells, CSC-like ovarian cancer cell lines, and liver CSCs. In GSCs, SIRT1 is required not only for the maintenance of stem cells, but also for oncogenic transformation through suppressing p53-dependent tumor surveillance [73]. Silencing of SIRT1 significantly enhances the sensitivity of CD1331 GSCs to radiation and increases the effectiveness of radiotherapy in the inhibition of xenografted CD1331 GSCs [74]. In BCSCs, SIRT1 is a direct target of miR-34a via its highly conserved 30 -UTR [75]. Low levels of miR-34a and high levels of SIRT1 are important for the expression of BCSC markers, maintenance of BCSC pool, and formation of mammosphere in vitro, as well as tumor burden in xenografts [75]. In colorectal CD1331 CSC-like cells, SIRT1 promotes colony and sphere formation in vitro, and enhances tumorigenesis of colorectal cancer cells in vivo by stimulating the expression of several stemness-associated genes [76]. In addition, SIRT1 promotes the hypoxia-induced CSC-like properties in human ovarian cancer cell lines [77]. SIRT1 is also highly expressed in liver CSCs and is important to maintain stemness properties or self-renewal and tumorigenic potential of liver CSCs [78,79]. Mechanistically, SIRT1 enhances SOX2 expression by reducing c-Myc USP22 SRT1720 TV-6 Ac Ac

LSCs Proliferation

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Sox2 Complex I Liver CSCs Self-renewal Tumorigenic potential

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Proliferation Adhesion TGF-E signaling

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Liver CSCs Stemness

FIGURE 2.3 SIRT1 regulates the stemness and self-renewal of CSCs. In BCSCs, SIRT1 is under negative control of miR-34a and is important to promote the expression of stem cell markers and maintenance. In liver CSCs, SIRT1 functions to promote Sox2 expression and mitochondrial respiration, which are important for liver CSCs self-renewal, tumorigenic potential, and stemness. Finally, SIRT1 is highly expressed in LSCs, either by increase in expression or by c-Myc/USP22-mediated stabilization, to inhibit p53 signaling and enhance mitochondrial gene expression and mitochondrial respiration via PGC-1α, which are important for LSC survival and proliferation. Inhibition of SIRT1 activity by TV-6 suppresses tumorigenic activity of LSCs in vitro and in vivo. In contrast, in MDS HSPCs, SIRT1 is repressed by miR-9 and miR-34a. Expression of SIRT1 or activation of SIRT1 by SRT1720 deacetylates TET2 and restores its function. This action increases 5hmC on the enhancers of a number of genes involved in proliferation, adhesion, and TGF-β signaling and represses their expression, thereby inhibiting MDS HSPC proliferation and functions.

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the DNA methylation level in the CpG islands of SOX2 promoter [78], and increases mitochondrial respiratory capacity by promoting the translocation of mitochondrial ribosomal protein S5 (MRPS5) to mitochondria through deacetylation [79]. Increased mitochondrial respiratory capacity is required for liver CSC stemness, and MRPS5 is critical to promoting mitochondrial respiratory capacity via promoting the function of Complex-I and generation of NAD1 [79]. Several studies from the McCormack group indicate that SIRT1 is important for the survival and proliferation of leukemic stem cells (LSCs). Both chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are organized as a hierarchy, with small populations of self-renewing LSCs that give rise to the bulk of leukemic cells [8082]. The McCormack group found that SIRT1 protein level is highly expressed in LSCs from both CML and AML [81,82]. The mRNA level of SIRT1 is increased in CML, whereas in AML, SIRT1 protein stability is enhanced due to c-MYC induced overexpression of USP22, a protein deubiquitinase that stabilizes SIRT1 [46]. This increase in SIRT1 protein inhibits p53 signaling and enhances mitochondrial gene expression and mitochondrial respiration via PGC-1α, which are important for LSC survival and proliferation [8183]. Conversely, knocking down/out SIRT1 expression or inhibiting SIRT1 activity by Tenovin-6 (TV6), a small molecule inhibitor of SIRT1 [84], decreases LSC proliferation, enhances apoptosis, and impairs their colony-forming ability [81,82]. More interestingly, the combined use of TV6 with kinase inhibitors (imatinib for BCR-ABL tyrosine kinase, or AC220 for FLT3, a kinase that commonly duplicated in AML) [82,85], leads to an enhanced inhibition of LSCs and improved survival of animals receiving CML LSCs transplantation or xenografted with imatinib-resistant blast crisis CML patient sample [81,82]. Given that inhibition of SIRT1 has only minimal impact on normal human CD341 HSCs, SIRT1 provides a good candidate for targeting LSCs, and the synergetic treatment could potentially cure leukemia patients with normal p53 function. However, in contrast to its pro-proliferation and self-renewal function in LSCs, SIRT1 activation is important to disrupt maintenance of myelodysplastic syndrome (MDS) stem and progenitor cells (HSPC) [86]. MDS is a group of clonal hematopoietic disorders, characterized by morphological dysplasia and ineffective hematopoiesis, leading to cytopenias and a 30% risk of transformation to AML [87]. Sun et al. found that SIRT1 protein levels are kept low by miR-9 and miR-34a in MDS HSPCs. Genetic or pharmacological activation of SIRT1 by a SIRT1 agonist SRT1720 leads to deacetylation and activation of TET2, a safeguard against HSPC transformation, which increases 5-hydroxymethylcytosine (5hmC) on the enhancers of a number of genes involved in proliferation, adhesion, and TGF-β signaling and repress their expression. This action of SIRT1 inhibits MDS HSPC proliferation and functions [86]. Therefore, depending on its deacetylation targets, SIRT1 exerts distinct functions in different CSCs.

2.4 SIRT2 in stem cell biology 2.4.1 SIRT2 promotes differentiation of ESCs in vitro In contrast to SIRT1, SIRT2, a predominately cytosolic sirtuin, is highly expressed in differentiated somatic cells but not in PSCs [88], and is not essential for embryonic viability and postnatal development in mice [32]. SIRT2 is induced during RA-induced differentiation of mESCS, and represses GSK3β to promote differentiation [89], implying that SIRT2 is important for differentiation of ESCs. Cha et al. found that SIRT2 is the primary deacetylase that deacetylates and inhibits glycolytic enzymes in hESCs [88]. So, SIRT2 expression in hESCS is repressed by miR200c-5p to allow high flux of glycolysis [88], which is important for ESC growth and pluripotency maintenance [16,9092]. Induction/overexpression of SIRT2 in ESCs represses glycolysis and promotes differentiation, and inhibition of SIRT2 in fibroblasts promotes the reprogramming of human fibroblasts to iPSCs [88]. However, complete depletion of SIRT2 prevents generation of pluripotent stem cells from mouse embryonic fibroblasts (MEFs) [93]. Collectively, SIRT2 is critical in controlling metabolic switch between PSCs and differentiated cells in vitro.

2.4.2 SIRT2 promotes survival of CSCs SIRT2 has been shown to promote CSC function and survival. For example, in contrast to SIRT1 and SIRT3, which are expressed in both glioblastoma stem cells (GSCs) and NSCs, SIRT2 is exclusively restricted to GSCs [94]. In BCSCs, the activity of aldehyde dehydrogenase 1A1 (ALDH1A1), a marker commonly used to isolate stem cells, is a direct deacetylation substrate of SIRT2 [95]. Zhao et al. showed that ALDH1A1 low in acetylation

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displays a high ALDH1 activity and is capable of promoting self-renewal of BCSCs. They further found that Notch signaling activated ALDH1A1 through the induction of SIRT2, leading to ALDH1A1 deacetylation and enzymatic activation to promote proliferation BCSCs. In breast cancer xenograft models, replacement of endogenous ALDH1A1 with an acetylation mimetic mutant inhibited tumorigenesis and tumor growth [95].

2.5 SIRT3 in stem cell biology 2.5.1 SIRT3 maintains the pool and regenerative capacity of HSCs during aging SIRT3 is a mitochondrial sirtuin which deacetylates mitochondrial proteins and reduces oxidative stress [96]. SIRT3 is highly enriched in HSCs and is reduced with age, indicating an important role in aging [96]. Consistently, Brown et al. showed that SIRT3 is not required for normal HSC homeostasis in young mice, but is essential in aged mice [96]. Deletion of SIRT3 reduces the HSC pool in aged mice and compromises HSC self-renewal upon serial transplantation stress, which is in part due to hyperacetylation of SOD2 and subsequent increase in oxidative stress [96]. Overexpression of SIRT3 in aged HSCs reduces oxidative stress and rescues their reconstitution capacity, highlighting the link between mitochondrial function and HSCs, and the role of this surtuin in regulating the aging-associated degeneration [96].

2.6 SIRT6 in stem cell biology 2.6.1 SIRT6 epigenetically promotes proper lineage commitment of ESCs and animal development

Ln cP R ES S1

SIRT6 is a nuclear sirtuin evolutionally important for proper differentiation of ESCs (Fig. 2.4). SIRT6-deficient ESCs are defective in differentiation, forming small embryoid bodies (EBs) and exhibiting skewed differentiation toward neuroectoderm when induced to differentiation [97]. However, although SIRT6 represses glycolysis that is important for ESC self-renewal [16,9092] through deacetylation of histones [98], elevated glycolysis is not a causation for the observed developmental phenotypes in SIRT6 KO ESCs [97]. Instead, SIRT6 deacetylates

p53 (human) H19

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Activity independently Ac

H3K9Ac H3K56Ac

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?

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TET1/2 (5hmC) Neuroectoderm Differentiation (mouse, human)

PI3Ksignaling

NRF2targets Oct4

ESCs

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MSCs Stress resistance

HSCs Self-renewal Glycolysis Hypoxia response (mouse, monkey)

Repopulation capacity

FIGURE 2.4 SIRT6 epigenetically regulates proper lineage commitment of ESCs and animal development, and inhibits stemness and proliferation of HSCs and CSCs. In mouse, monkey, and human, SIRT6 represses expression of metabolic genes (particularly glycolytic genes), core pluripotent genes, and maternal imprinted lncRNA H19 through deacetylation of H3K9ac and K3K56ac. These actions of SIRT6 metabolically and epigenetically safeguard the balance between pluripotency and differentiation. In hESCs, a p53-targeted lncRNA, lncPRESS1, physically interacts with SIRT6 and prevents its chromatin localization, which in turn maintains high levels of H3K56ac and H3K9ac at promoters of pluripotency genes. Therefore, in contrast to SIRT1, SIRT6 is an evolutionally conserved regulator of ESC differentiation and animal development both in vitro and in vivo. Consistently, SIRT6 also functions to inhibit self-renewal of HSCs and to suppress cancer stem-like capacity in CSCs.

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H3K56ac and H3K9ac, thereby repressing expression of the core pluripotency genes (OCT4, SOX2, and NANOG) and promoting differentiation. In hESCs, SIRT6 is inhibited by a p53-targeted lncRNA, lncPRESS1 [99]. LncPRESS1 physically interacts with SIRT6 and prevents its chromatin localization, maintaining high levels of H3K56ac and H3K9ac at promoters of pluripotency genes [99]. Deletion of SIRT6 leads to high levels of H3K56ac and H3K9ac, and persistent expression of OCT4, SOX2, and NANOG in ESCs and EBs, thereby preventing differentiation [97]. Moreover, OCT4 and SOX2 enhance the expression of TET1 and TET2, which increase 5-hydroxymethylcytosine (5hmC), particularly on neural genes, and shift differentiation toward neuroectoderm [97]. Besides epigenetic regulation, SIRT6 also deacetylates p53 at lysine 381 to reduce the stability and activity of p53 [100]. Consistent with its role in ESC differentiation, SIRT6 is important for embryogenesis and animal development. SIRT6 knockout mice show developmental delay and premature death [97], and haploinsufficiency of Trp53 dramatically extends the life span of these mice [100]. Deletion of SIRT6 in cynomolgus monkey leads to hyperacetylation of histone, activating the long noncoding RNA H19 and resulting in prenatal developmental retardation and neonatal death [101]. A homozygous SIRT6 inactive mutation in human also leads to hyperacetylation of H3K9 and H3K56, dramatically elevating pluripotent genes and causing severe congenital anomalies and perinatal lethality [102]. Collectively, SIRT6 is critical in safeguarding the balance between pluripotency and differentiation [97].

2.6.2 SIRT6 controls regeneration and stress resistance in HSCs and mesenchymal stem cells SIRT6 is also important in maintaining HSC quiescence and long-term repopulation capacity by inhibiting HSC proliferation. Specific depletion of SIRT6 in adult mouse HSCs leads to enhanced H3K56ac level and increases the expression of transcription factors in the Wnt pathway, which results in a twofold expansion of HSPC [103]. Enhanced proliferation makes HSCs more prone to depletion, and impairs their long-term repopulation capacity [103]. In addition, SIRT6 helps to maintain the functionality of MSCs through ameliorating stress in vitro [104]. SIRT6-deficient human MSCs have increased ROS levels and elevated vulnerability to oxidative injury, and exhibit accelerated cell attrition after implantation to the muscles of immunodeficient mice [104]. This action of SIRT6, again, has been attributed to its deacetylation activity on H3K56ac, which directly upregulates a number of NRF2-regulated antioxidant genes by recruiting RNAP II to their promoters [104]. Although it remains unclear how a deacetylase that usually represses gene expression through histone deacetylation acts as a coactivator to promote expression of antioxidant genes in MSCs, this study indicates that SIRT6 is important for MSC stress resistance and delay of aging.

2.6.3 SIRT6 suppresses stemness of CSCs In contrast to the prostemness function of SIRT1 and SIRT2 in CSCs, SIRT6 appears to suppress cancer stemlike capacity in breast, lung, and colorectal cancer cells [105] and inhibit colorectal CSC proliferation [106], which is consistent with its reported tumor-suppressing activity [107]. Ioris et al. reported that overexpression of SIRT6 reduces growth, progression, and grade of breast tumors in a mouse model with PI3K activation, by suppressing the PI3K-boosted glycolysis/pentose phosphate pathway and hindering their stemness. This anticancer stemness action of SIRT6 requires the activation of PI3K, as ablation of a PI3K-activating mutation in otherwise isogenic cancer cells is sufficient to convert SIRT6-sensitive into SIRT6-insensitive cells [105]. However, intriguingly, although the anticancer stemness action of SIRT6 is in line with its pluripotency suppressing activity in ESCs [97], SIRT6 overexpression suppresses PI3K signaling at the transcriptional level and antagonizes tumor sphere formation independent of its histone deacetylase activity in the PI3K activation cancer model [105]. Additional studies are required to dissect the activity dependent and independent mechanisms of SIRT6 in repressing stemness of different types of stem cells.

2.7 SIRT7 in stem cell biology 2.7.1 SIRT7 regulates embryogenesis and life span through maintenance of genome stability SIRT7, a nuclear sirtuin enriched in the nucleolus, also plays a role in animal development [33]. SIRT7 is important in maintaining genome stability. When recruited to sites of DNA damage, SIRT7 deacetylates

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H3K18ac, helping recruitment of damage response factors to DNA double-strand breaks and promoting DNA nonhomologous end joining repair [33]. SIRT7-deficient pups display defective embryogenesis and growth retardation, and are born at sub-Mendelian ratios. More than 20% of SIRT7 null mice die within the first month of life, and the remaining knockouts show signs of accelerated aging with dramatically reduced life span [33].

2.7.2 SIRT7 regulates quiescence and regenerative capacity of HSCs SIRT7 is also important in modulating HSC quiescence and regenerative capacity through regulating metabolic homeostasis [108]. The expression pattern of SIRT7 in HSCs is similar to that of SIRT3, with high expression in HSCs and reduction with age [108], which indicates a critical role in regulating HSC aging. Quiescent HSCs are metabolically inactive. When induced to proliferate, they readily turn into a metabolically active state associated with a dramatic increase of mitochondrial mass. Mohrin et al., found that SIRT7, which is induced by mitochondrial protein folding stress (PFSmt), interacts with nuclear respiratory factor 1 (NRF1), a master regulator of mitochondria, to inhibit the expression of mitochondrial ribosomal proteins and mitochondrial translation factors [108]. SIRT7 knockdown cells increase mitochondria mass and proliferation, demonstrating that SIRT7 is important for preserving HSC quiescence [108]. Consistently, SIRT7 KO HSCs exhibit phenotypes of aging in vivo, including increased PFSmt and apoptosis, loss of quiescence, reduced repopulation capacity, and myeloid-biased differentiation. Conversely, upregulation of SIRT7 improves the regenerative capacity of aged HSCs [108].

2.8 Concluding remarks and future perspectives Emerging evidence reveals important functions of the sirtuin family in regulation of self-renewal, stemness maintenance, pluri-/multipotency, and differentiation of both PSCs and ASCs. Dysfunction and dysregulation of sirtuins in stem cells are linked to a number of human diseases, including developmental defects, degenerative diseases, and cancer. Therefore, it is clear that stem cell sirtuins are at the crossroads of development, aging, and cancer. Given the essential role of NAD1 in diverse cellular processes, including energy metabolism, redox sensing, DNA repair, and genome stability [109], it is not surprising that stem cells harness the sirtuin family of NAD1-dependent enzymes to tightly link their metabolic plasticity to epigenetics, transcription, genome stability, and stress resistance in response to developmental and environmental cues. However, despite their common dependence on cellular NAD1, different sirtuins display cell type-specific and/or stage-dependent impacts on stem cell biology. On the one hand, different sirtuins often have distinct, even contrasting, functions in the same stem cell type. For example, as nuclear sirtuins in ESCs, SIRT1 maintains pluripotency and represses differentiation genes, whereas SIRT6 suppresses pluripotency genes and is critical for their proper lineage commitment upon differentiation. This phenomenon is likely more consistent with their expression dynamics and/or substrate specificities than NAD1 sensing. On the other hand, the same sirtuin may elicit differential impacts in different stem cells. For instance, SIRT6 maintains the quiescent state and long-term regeneration capacity of ASCs, but suppresses the stemness of ESCs. Much work is still needed to comprehend how different members of sirtuins integrate distinct environmental cues via their differential dosages, distinct sensitivities to NAD1, diverse substrates, and interacting partners at various subcellular compartments to coordinate environmental influence on stem cell activities. It is also worth noting that mitochondrial sirtuins, SIRT3 in particular, are crucial defenders from oxidative stress in various cell types, including HSCs, during the process of aging, yet evidence for their contribution to the maintenance of PSCs is still lacking. This is likely due to the fact that PSCs have evolved a variety of mechanisms to protect themselves from ROS, including their preferential use of glycolysis instead of oxidative phosphorylation to reduce ROS production [25,110] and their employment of a number of alterative mechanisms to protect against oxidative stress [111]. Consistently, PSCs such as ESCs have relatively low expression of mitochondrial sirtuins [26]. Nevertheless, given the prevalence of obesity and metabolic syndrome in the reproductive population as well as the increasing parental age in modern society, it will be interesting to study whether mitochondrial sirtuins can regulate the maintenance and survival of PSCs, particularly iPSCs and germline stem cells, under these oxidative stress-associated conditions. Recent advancements in the field have shown that lysine acetylation is just one type of a widespread protein modification known as lipid lysine acylation. These short-chain and long-chain lipids are generated

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by completely different metabolic pathways, and distinct protein acylations are associated with differential regulation of gene transcription, particularly during germ cell development [112,113]. Intriguingly, in addition to deacetylation, sirtuins have been shown to have activities to remove lipid acyl-groups from protein lysine side chains [112,114116]. Further studies on sirtuin-mediated protein deacylation in stem cells will shed light on the functions of these newly discovered protein modifications in regulating stem cell biology.

References [1] He W, et al. Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol Metab 2012;23(9):46776. [2] Choudhary C, et al. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol 2014; 15(8):53650. [3] Wagner GR, Hirschey MD. Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases. Mol Cell 2014;54(1):516. [4] Imai SI, Guarente L. It takes two to tango: NAD(1) and sirtuins in aging/longevity control. NPJ Aging Mech Dis 2016;2:16017. [5] Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 2000;273(2):7938. [6] Tanno M, et al. Nucleocytoplasmic shuttling of the NAD 1 -dependent histone deacetylase SIRT1. J Biol Chem 2007;282(9):682332. [7] Mostoslavsky R, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2006;124(2):31529. [8] Ford E, et al. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev 2006;20(9):107580. [9] Verdin E, et al. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 2010;35(12):66975. [10] van de Ven RAH, et al. Mitochondrial sirtuins and molecular mechanisms of aging. Trends Mol Med 2017;23(4):32031. [11] Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 2014;25(3):13845. [12] Satoh A, et al. The brain, sirtuins, and ageing. Nat Rev Neurosci 2017;18(6):36274. [13] Dang CV. Links between metabolism and cancer. Genes Dev 2012;26(9):87790. [14] Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012;21(3):297308. [15] Carey BW, et al. Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 2015;518(7539):41316. [16] Folmes CD, et al. Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 2012;11(5):596606. [17] Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 2013;13(8):57283. [18] Wang J, et al. Dependence of mouse embryonic stem cells on threonine catabolism. Science 2009;325(5939):4359. [19] Shiraki N, et al. Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab 2014; 19(5):78094. [20] Cai L, et al. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol Cell 2011; 42(4):42637. [21] Wellen KE, et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009;324(5930):107680. [22] Xu W, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011;19(1):1730. [23] Shyh-Chang N, et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 2013; 339(6116):2226. [24] Moussaieff A, et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab 2015;21(3):392402. [25] Folmes CD, et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 2011;14(2):26471. [26] Efroni S, et al. Global transcription in pluripotent embryonic stem cells. Cell Stem Cell 2008;2(5):43747. [27] McBurney MW, et al. The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 2003;23(1):3854. [28] Cheng HL, et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A 2003;100(19):107949. [29] Haigis MC, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006;126(5):94154. [30] Lombard DB, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 2007;27(24):880714. [31] Vakhrusheva O, et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res 2008;102(6):70310. [32] Kim HS, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 2011; 20(4):48799. [33] Vazquez BN, et al. SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair. EMBO J 2016; 35(14):1488503. [34] Signer RA, Morrison SJ. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell 2013;12(2):15265. [35] Biteau B, et al. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 2011;9(5):40211. [36] Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med 2011;17(3):31319. [37] Bao B, et al. Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy. Curr Protoc Pharmacol 2013; Chapter 14, Unit 14 25. [38] Nassar D, Blanpain C. Cancer stem cells: basic concepts and therapeutic implications. Annu Rev Pathol 2016;11:4776. [39] O’Callaghan C, Vassilopoulos A. Sirtuins at the crossroads of stemness, aging, and cancer. Aging Cell 2017;16(6):120818. [40] Saunders LR, et al. miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues. Aging (Albany NY) 2010;2(7):41531. [41] Tang S, et al. Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. EMBO J 2017;36(21):317593.

I. Sirtuins and metabolic disease

36

2. Sirtuins in metabolic and epigenetic regulation of stem cells

[42] Coussens M, et al. Sirt1 deficiency attenuates spermatogenesis and germ cell function. PLoS One 2008;3(2):e1571. [43] Wang RH, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 2008; 14(4):31223. [44] Liu C, et al. Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice. Development 2017; 144(3):44151. [45] Tang S, et al. SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation. Mol Cell 2014;55(6):84355. [46] Lin Z, et al. USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Mol Cell 2012;46(4):48494. [47] Satoh A, et al. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J Neurosci 2010;30(30):1022032. [48] Bell EL, et al. SirT1 is required in the male germ cell for differentiation and fecundity in mice. Development 2014;141(18):3495504. [49] Zhang ZN, et al. Oct4 maintains the pluripotency of human embryonic stem cells by inactivating p53 through Sirt1-mediated deacetylation. Stem Cell 2014;32(1):15765. [50] Williams EO, et al. Sirtuin 1 promotes deacetylation of Oct4 and maintenance of naive pluripotency. Cell Rep 2016;17(3):80920. [51] Heo J, et al. Sirt1 regulates DNA methylation and differentiation potential of embryonic stem cells by antagonizing Dnmt3l. Cell Rep 2017;18(8):193045. [52] Suetake I, et al. DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J Biol Chem 2004;279(26):2781623. [53] Gowher H, et al. Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)-methyltransferases by Dnmt3L. J Biol Chem 2005;280(14):133418. [54] Jia D, et al. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 2007;449(7159):24851. [55] Calvanese V, et al. Sirtuin 1 regulation of developmental genes during differentiation of stem cells. Proc Natl Acad Sci U S A 2010; 107(31):1373641. [56] Abdelmohsen K, et al. Posttranscriptional orchestration of an anti-apoptotic program by HuR. Cell Cycle 2007;6(11):128892. [57] Jang J, et al. SIRT1 enhances the survival of human embryonic stem cells by promoting DNA repair. Stem Cell Rep 2017;9(2):62941. [58] De Bonis ML, et al. SIRT1 is necessary for proficient telomere elongation and genomic stability of induced pluripotent stem cells. Stem Cell Rep 2014;2(5):690706. [59] Han MK, et al. SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization. Cell Stem Cell 2008;2(3):24151. [60] Ou X, et al. SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cell 2014;32(5):118394. [61] Liu B, et al. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria. Cell Metab 2012;16(6):73850. [62] Choi Y, et al. Enhancement of mesenchymal stem cell-driven bone regeneration by resveratrol-mediated SOX2 regulation. Aging Dis 2019;10(4):81833. [63] Igarashi M, Guarente L. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell 2016; 166(2):43650. [64] Yilmaz OH, et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 2012;486(7404):4905. [65] Ryall JG, et al. The NAD(1)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell 2015;16(2):17183. [66] Prozorovski T, et al. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 2008;10(4):38594. [67] Ma CY, et al. SIRT1 suppresses self-renewal of adult hippocampal neural stem cells. Development 2014;141(24):4697709. [68] Rafalski VA, et al. Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nat Cell Biol 2013; 15(6):61424. [69] Seita J, Weissman IL. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med 2010;2(6):64053. [70] Leko V, et al. SIRT1 is dispensable for function of hematopoietic stem cells in adult mice. Blood 2012;119(8):185660. [71] Ou X, et al. SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse. Blood 2011;117(2):44050. [72] Singh SK, et al. Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance. J Exp Med 2013;210(5):9871001. [73] Lee JS, et al. SIRT1 is required for oncogenic transformation of neural stem cells and for the survival of “cancer cells with neural stemness” in a p53-dependent manner. Neuro Oncol 2015;17(1):95106. [74] Chang CJ, et al. Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression. Biochem Biophys Res Commun 2009;380(2):23642. [75] Ma W, et al. Dysregulation of the miR-34a-SIRT1 axis inhibits breast cancer stemness. Oncotarget 2015;6(12):1043244. [76] Chen X, et al. High levels of SIRT1 expression enhance tumorigenesis and associate with a poor prognosis of colorectal carcinoma patients. Sci Rep 2014;4:7481. [77] Qin J, et al. Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression. Sci Rep 2017;7(1):10592. [78] Liu L, et al. SIRT1-mediated transcriptional regulation of SOX2 is important for self-renewal of liver cancer stem cells. Hepatology 2016;64(3):81427. [79] Wei Z, et al. Sirtuin-1/mitochondrial ribosomal protein S5 axis enhances the metabolic flexibility of liver cancer stem cells. Hepatology 2019;70(4):1197213. [80] Patel JP, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366(12):107989.

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References

37

[81] Li L, et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 2012;21(2):26681. [82] Li L, et al. SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. Cell Stem Cell 2014;15(4):43146. [83] Abraham A, et al. SIRT1 regulates metabolism and leukemogenic potential in CML stem cells. J Clin Invest 2019;129(7):2685701. [84] Lain S, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 2008;13(5):45463. [85] Kindler T, et al. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 2010;116(24):5089102. [86] Sun J, et al. SIRT1 activation disrupts maintenance of myelodysplastic syndrome stem and progenitor cells by restoring TET2 function. Cell Stem Cell 2018;23(3):35569 e9. [87] Sperling AS, et al. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer 2017;17(1):519. [88] Cha Y, et al. Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis. Nat Cell Biol 2017;19(5):44556. [89] Si X, et al. Activation of GSK3beta by Sirt2 is required for early lineage commitment of mouse embryonic stem cell. PLoS One 2013; 8(10):e76699. [90] Zhang J, et al. Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell 2012;11(5):58995. [91] Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 2014;15(4):24356. [92] Teslaa T, Teitell MA. Pluripotent stem cell energy metabolism: an update. EMBO J 2015;34(2):13853. [93] Kim AY, et al. SIRT2 is required for efficient reprogramming of mouse embryonic fibroblasts toward pluripotency. Cell Death Dis 2018;9(9):893. [94] Sayd S, et al. Sirtuin-2 activity is required for glioma stem cell proliferation arrest but not necrosis induced by resveratrol. Stem Cell Rev 2014;10(1):10313. [95] Zhao D, et al. NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells. J Clin Invest 2014; 124(12):545365. [96] Brown K, et al. SIRT3 reverses aging-associated degeneration. Cell Rep 2013;3(2):31927. [97] Etchegaray JP, et al. The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nat Cell Biol 2015;17(5):54557. [98] Zhong L, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010;140(2):28093. [99] Jain AK, et al. LncPRESS1 is a p53-regulated LncRNA that safeguards pluripotency by disrupting SIRT6-mediated de-acetylation of histone H3K56. Mol Cell 2016;64(5):96781. [100] Ghosh S, et al. Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice. eLife 2018;7:e32127. [101] Zhang W, et al. SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature 2018;560(7720):6615. [102] Ferrer CM, et al. An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes Dev 2018; 32(56):37388. [103] Wang H, et al. SIRT6 controls hematopoietic stem cell homeostasis through epigenetic regulation of Wnt signaling. Cell Stem Cell 2016;18(4):495507. [104] Pan H, et al. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res 2016;26(2):190205. [105] Ioris RM, et al. SIRT6 suppresses cancer stem-like capacity in tumors with PI3K activation independently of its deacetylase activity. Cell Rep 2017;18(8):185868. [106] Liu W, et al. SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A. Oncol Lett 2018;15(4):536874. [107] Sebastian C, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 2012;151(6):118599. [108] Mohrin M, et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 2015;347(6228):13747. [109] Canto C, et al. NAD(1) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab 2015;22(1):3153. [110] Simsek T, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 2010; 7(3):38090. [111] Tower J. Stress and stem cells. Wiley Interdiscip Rev Dev Biol 2012;1(6):789802. [112] Sabari BR, et al. Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol 2017;18(2):90101. [113] Sabari BR, et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol Cell 2015; 58(2):20315. [114] Bheda P, et al. The substrate specificity of sirtuins. Annu Rev Biochem 2016;85:40529. [115] Tasselli L, et al. SIRT6: novel mechanisms and links to aging and disease. Trends Endocrinol Metab 2017;28(3):16885. [116] Anderson KA, et al. SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab 2017;25(4):83855 e15.

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C H A P T E R

3 Sirtuins and metabolic regulation: food and supplementation Se´rgio Henrique Sousa Santos1,2, Victor Hugo Dantas Guimara˜es2, Janaina Ribeiro Oliveira2 and Luiz Fernando Rezende2 1

Postgraduate Program in Food and Health; Food Engineering School, Agricultural Sciences Institute (ICA), Federal University of Minas Gerais (UFMG), Montes Claros, Brazil 2Laboratory of Health Science, Postgraduate Program in Health Sciences; State University of Montes Claros (UNIMONTES), Montes Claros, Brazil O U T L I N E 3.1 Introduction

39

3.2 Tissue-specific sirtuin-modulated metabolic regulation 3.2.1 Liver 3.2.2 Adipose tissue 3.2.3 Heart and skeletal muscle 3.2.4 Kidneys 3.2.5 Pancreas 3.2.6 Brain

42 42 42 43 43 44 44

3.3 Nutrition as a therapeutic model for sirtuin regulation 3.3.1 Polyphenols

44 45

3.4 Resveratrol

47

3.5 Gallic acid

48

3.6 Nonresveratrol related sirtuin activators

48

3.7 Food and sirtuins 3.7.1 Mediterranean diet 3.7.2 Berberin 3.7.3 Green cardamom 3.7.4 Cocoa 3.7.5 Indole-3-carbinol 3.7.6 Xanthigen

50 50 51 51 51 51 52

3.8 Conclusion

52

References

52

3.1 Introduction Economic and cultural changes observed in the last decade have substantially modified people’s way of life. Several factors, such as lifestyle, eating habits, and stress, have been indicated as prevalent issues in the increased levels of nontransmissible chronic diseases, including obesity [1]. Obesity is a major health issue worldwide with a current high occurrence and an estimated 2.3 billion people will be affected worldwide by 2025 [2]. The condition is characterized by excessive body fat deposits associated with reduced energy expenditure and/or food intake imbalance [3]. Excessive body fat itself constitutes an important metabolic syndrome (MS) component, a condition associated with serious complications such as type 2 diabetes (DM2), hypertension, hypertriglyceridemia, reduced glucose tolerance, increased cholesterol, impaired insulin sensitivity, nonalcoholic fatty liver disease (NAFLD), and cardiovascular diseases [4,5].

Sirtuin Biology in Cancer and Metabolic Disease. DOI: https://doi.org/10.1016/B978-0-12-822467-0.00003-6

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© 2021 Elsevier Inc. All rights reserved.

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3. Sirtuins and metabolic regulation: food and supplementation

As previously stated, obesity plays a central role in MS onset. Increased caloric intake promotes adipocytes hypertrophy and abnormal adipokines secretion [6]. Those changes can be observed in the white adipose tissue (WAT) via promotion of the secretion of nonesterified fatty acids (NEFAs) in the circulatory system, impairing peripheral tissues’ insulin signaling and reducing its sensitivity [79]. Moreover, elevated serum NEFAs increase expression of several proinflammatory cytokines, such as tumoral necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) [10] (Fig. 3.1). Those changes may compromise the function of several organs, lower the individual life quality and modulate many enzymes, amongst which we highlight the sirtuins (Sirt). Sirtuins have recently become important targets in the field of health research as modulators of several metabolic diseases, like obesity and its complications [11,12]. The discovery of sirtuin’s chemical structure as well as its regulators (either inhibitors or activators) made possible the identification of sirtuin’s actions over many diseases and its possible therapeutic role [13]. Many authors suggest sirtuin modulation as a possible pathway for the control and management of several age-related diseases, such as diabetes, cancer, cardiovascular and neurodegenerative disorders [14], each somehow associated with pathological inflammatory conditions [15]. Sirtuins are found everywhere in humans (Fig. 3.2), that is, SIRT1 is expressed in brain, liver, pancreas, adipose tissues, skeletal muscle, and heart [16]. Sirtuins may function as deacetylases and/or ADP-ribosyltransferases. Deacetylases-activated sirtuins remove acetylated lysine residues acetyl groups from several target proteins, including histones and transcription factors. Sirtuin 1 (SIRT1) and Sirtuin 3 (SIRT3) are considered crucial to the control of metabolic processes. They are located in the nucleus and mitochondria, respectively, and are expressed in a wide variety of tissues with numerous target proteins [17].

FIGURE 3.1 Obesity development and metabolic disorders: Obesity is characterized by excessive body fat. Increased adiposity leads to adipocyte hypertrophy, which in turn starts to secrete more adipokines. Among the adipokines we highlight MCP-1, which promotes the recruitment of monocytes (Mφ) from the bloodstream, which are released from adipose tissue and may be differentiated into the Mφ1 lineage, causing inflammation, through the interleukins secretion associated with tumor necrosis factors (TNF). Adipokine secretion deregulation, as well as inflammatory factors, may lead to organ dysfunction, compromising their tasks and leading to the development of type 2 diabetes mellitus (DM2), cardiovascular diseases (CVDs), cancer, nonalcoholic fatty liver disease (NAFLD), insulin resistance, and other coexisting metabolic changes in the metabolic syndrome.

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FIGURE 3.2 Sirtuin expression in many organs and its role over metabolic physiological regulation.

SIRT1 and SIRT3 coordinately increase cellular energy reserves, thus maintaining cell energy homeostasis. Any defects on SIRT-controlled pathways result in many metabolic disturbances. Therefore genetic or pharmacological sirtuin activations might lead to metabolic benefits ultimately protecting mice from diet-induced obesity, DM2, and NAFLD [17]. Mammal SIRT1 deacetylation is involved in a series of functions, such as apoptosis, cell cycle, circadian rhythm, mitochondrial function, and metabolism-related target proteins. Currently, researchers are focused on SIRT1’s impact on glucose homeostasis and energy balance [18]. While SIRT1 plays an important role in metabolic function, SIRTs 3 and 5 are located in the mitochondria, thus controlling mitochondrial energy metabolism itself. As the most well-known and studied of the mitochondrial sirtuins, SIRT3 deacetylates several mitochondrial proteins, thus also playing a role in ATP production. Mammal sirtuins are regulated not only by the NAD1/NADH ratio or cellular stressors, but also by transcription/translation-related endogenous proteins as well as many microRNAs [16]. SIRT1 interacts with and regulates a number of histones and nonhistones protein substrates. The huge variety of endogenous targets is associated with the diverse array of biological functions controlled by SIRT1, being involved in age and development, energetic metabolism, inflammation, and DNA double-strand repair, amongst others [18]. Several mice models were used to elucidate and characterize sirtuin’s metabolic functions. Whole body SIRT1-KO mice present low birth weight and don’t live past the initial postnatal stage, while race-specific SIRT-KO mice exhibit developmental and metabolic abnormalities, such as cardiac defects and reduced motor activity, but also improved glucose homeostasis. Some studies opted for a tissue-specific knockout model, such as liver-specific SIRT1-KO mice, although many of the results are often contradictory. Moreover, not only SIRT1 knockdown but also overexpression have been used as a model of investigation, such as the whole body SIRT1 overexpression mice that showed a resistance to high-fat diet (HFD)-induced metabolic dysfunction as well as studies on other sirtuins, specially their importance in mitochondrial metabolic regulation [17,18].

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3.2 Tissue-specific sirtuin-modulated metabolic regulation 3.2.1 Liver In the liver, SIRT1 has several deacetylation targets affecting gluconeogenesis and fat homeostasis. Many of those deacetylation events present opposite effects, thus highlighting the complex nature of SIRT1 function in this organ. For example, SIRT1 deacetylates two distinct gluconeogenesis coactivators with opposite functions, while PGC-1α is an activator [19], CRTC2 acts as an ubiquination and degradation factor [20]. It is postulated then that SIRT1 enacts temporal changes during fasting periods, alternating between an initial CRTC2-mediated mechanism to a posterior PGC-1a induced at a later stage. SIRT1 is reduced at the right moment because the SIRT1 promoter itself is regulated by CRTC2 mediated by the CREB transcription factor [21]. The lower CRTC2 and subsequent SIRT1 thus establish a lower activity level suitable for SIRT1 substrate and PGC-1α at later fasting periods. As for the fat homeostasis, SIRT1 deacetylates LXR nuclear receptor [22] to activate SREBP1 gene for synthesis. However, SIRT1 deacetylates SREBP1 itself to inhibit its activity [23]. Other SIRT1 substrates include FXR nuclear receptor for biliary synthesis [24] and LKB1 linking SIRT1 and AMPK [25,26], as previously described. In vitro studies showed that SIRT1 increases fatty acids oxidation through PPARα receptor activation [27]. Hepatocytesspecific SIRT1-KO mice showed glucose overproduction, chronic hyperglycemia, and increased ROS production, thus resulting in mTORC2/AKT-mediated oxidative stress and consequently insulin resistance [28]. Moreover, numerous studies examined the role of hepatic SIRT1 on many alimentary conditions, and found that liverspecific SIRT1-KO leads to physiological hypersensitivity to a fat-rich diet [2932], with the exception being that overexpression protects against hepatic steatosis [33,34]. Accordingly, fat-rich diet-induced inflammation leads to JNK1 kinase-induced SIRT1 phosphorylation and its subsequent degradation, as observed in WAT [35]. SIRT3 has several targets in hepatocytes. In fasting conditions, SIRT3 is increased and promotes fatty acids oxidation [36], while also activating the urea cycle [22] and liver ketogenesis [37]. SIRT3 inhibition in a fatty diet-fed mice results in earlier obesity, hyperlipidemia, insulin resistance, and hepatic steatosis. It has also been shown that both obesity as well as a chronic HFD reduced SIRT3 activity, induced hyperacetylation of several mitochondrial proteins, and impaired mitochondrial function [3840]. SIRT3-KO mice fed a methionine/choline deficient (MCD) diet showed elevated ALT serum levels, increased hepatic content, and increased expression of inflammatory genes as well as reduced fibrogenic activity (SOD2). However, SIRT3 overexpression resulted in the opposite effects, suggesting that SIRT3-KO aggravates MCD-induced NASH, while SIRT3 overexpression attenuates the MCD-induced phenotype [41,42]. Liver SIRT4 shows an antagonistic role to SIRT1 given that its Knockout protects against HFD-induced hepatic steatosis [43], possibly because SIRT4 deacetylates and inhibits malonyl-CoA decarboxylase (MCD1), converting malonyl-CoA to acetyl-CoA [44], thus inhibiting the accumulation of malonyl-CoA, the main precursor for fat synthesis, as well as reducing SIRT4 levels in RC. Finally, hepatic SIRT6, like SIRT1, seems protective, given that two studies shows that SIRT6-KOs are more prone to hepatic steatosis [42,45,46].

3.2.2 Adipose tissue Adipose tissue has been increasingly implicated in energy homeostasis, with SIRTs 1, 2, and 6 directly involved in adipocytes function; SIRT1 has been the most explored. SIRT1 increases adiponectin expression, an important adipokine for energy metabolism, at least in part through FOXO1 protein deacetylation [47], which lowers susceptibility to obesity and diabetes, increases insulin sensitivity, and promotes glucose homeostasis. SIRT1 also inhibits white adipocytes formation and activates lipolysis through PPAR-γ suppression, an important regulator in adipocytes [48]. While SIRT1 and NAD1 are both induced in CR mice WAT [33], SIRT1 is reduced in obese mice [49] and human WATs [50]. A possible mechanism for SIRT1 inhibition in obese animals is suggested by the findings that HFD triggers SIRT1 cleavage in WAT by Caspase 1 [49]. WAT-specific SIRT1-KO mice are prone to diabetes, possibly because the “first blow” in that direction has already been taken. Interestingly, SIRT2 also plays a functional role in adipocytes biology through preadipocytes differentiation [51]. More data corroborate the hypothesis that SIRT1 in the WAT promotes metabolic health through reduced fat deposits. SIRT1 promotes fat mobilization from the WAT to bloodstream during fasting periods in order to facilitate its oxidation in liver and muscle [48]. SIRT1 also promotes WAT browning, which might lead to in situ fat oxidation [52]. Consistently, SIRT1 inhibition in WAT is associated with inflammatory processes and macrophage recruitment [53]. A deacetylation target from SIRT1 in WAT is the nuclear receptor PPARγ [54]. SIRT1 affects

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gene expression from a PPARγ target genes subset restricting differentiation of preadipocytes precursor cells [48]. Finally, SIRT1 transgenic mice show higher insulin sensitizing adipokines [55]. Further roles for sirtuins in adipokines production and endocrine signaling between WAT and hypothalamus remain a fascinating study subject. SIRT2 may also inhibit adipocytes differentiation, at least in part through FOXO1 protein deacetylation [56]. Moreover, SIRT2 activates FOXO3 in adipocytes, thus reducing oxidative stress [57]. SIT6 has been found to be a negative regulator for DGAT1 gene expression, which reduces triglycerides biosynthesis [58].

3.2.3 Heart and skeletal muscle Studies suggest that calorie restriction (CR); physical exercise, and resveratrol may induce mitochondrial biosynthesis and increase mice and human skeletal muscle stress tolerance [5961], with at least three pathways being implicated in those effects. Firstly, skeletal muscle endothelial nitric oxide synthase (eNOS) activity is induced by CR in mice and humans [62,63]. Given that SIRT1 is known to deacetylate and activate eNOS [64], SIRT1 induction in skeletal muscle might help to explain the whole chain of events. eNOS2/2 mice show no CR-induced mitochondrial activity [62], proving the involvement of eNOS. Secondly, PGC-1α deacetylation is also induced by CR or resveratrol and jumpstarts mitochondrial biogenesis [19,65]. Thirdly, CR-induced adipokine binds to its skeletal muscle receptor and stimulates SIRT1/AMPK axis causing Ca21 release and subsequent activation of AMPKkinase calmodulin-dependent protein kinase, a pathway that can also be activated by physical exercise. Glucose effects over cultivated skeletal muscle cells are dependent on SIRT1AMPKFOXO1 interaction, AMPK and FOXO1 [66,67], and, unsurprisingly, skeletal muscle tissues-specific SIRT1-KO impairs CR-induced physiological changes [68]. As for the heart, studies in mice showed that SIRT1’s gain or loss of function protects against oxidative stress such as in ischemiareperfusion injuries (IRI) [69,70]. SIRT1 may also protect against moderate levels of specific cardiac overexpression but be harmful at higher levels [71]. Protection against hypertrophy might involve a pathway including PPARα and fat oxidation [72]. Although, surprisingly, a study has shown that SIRT1 or PPARα haplosufficiency protected against pressure overloadinduced hypertrophy [73]. Notably, CR induced SIRT1 nuclear location through a mechanism requiring eNOS, which was associated with ischemia tolerance [74]. SIRT1 and eNOS might comprise a self-reinforcing activity loop, similar to SIRT1 and AMPK. As for other sirtuins, it has been shown that SIRT6 attenuates AKT signaling in heart, protecting against hypertrophy [75], in which case SIRT6 acts as an IFG-activated gene corepressor by binding to c-jun transcription factor. Finally, a recent study showed that mice knockout for a complex 1 subunit in the heart had increased NADH and SIRT3 inhibition [76], rendering those rats more susceptible to cardiac insufficiency, thus reinforcing SIRT3’s importance for proper cardiac function [77].

3.2.4 Kidneys Many studies have indicated SIRT1-mediated renal function protection, starting with the reported oxidative stress mitigation by SIRT2 in HK-2 cells [78]. SIRT1 genetic activation, either through transgenic mice or STACs administration, protects those animals against several renal injuries models [7982]. SIRT1 also mitigates fibrosis subsequent to acute renal failure by Smad4 deacetylation and TGF-β signaling suppression [83]. Moreover, SIRT1 is required for renal protection against RC-induced hypoxia, in this case by FOXO3 deacetylation and autophagy activation [84]. Finally, CR is also a renal protector in a rat model of diabetes, associated with SIRT1 activation and NF-κB deacetylation [85]. A recent study suggests a novel communication scheme between renal compartments mediated by SIRT1. In a compartment consisting of proximal tubule cells, SIRT1 establishes nicotinamide mononucleotide (NMN) precursor levels. Released NMN activates SIRT1 in a different renal compartment, constituted by podocytes, to activate stress resistance. This circuit net effect is kidney protection and diabetic albuminuria inhibition [86]. Conversely, SIRT1 might contribute to autosomic-dominant polycystic kidney disease (ADPKD), and hereditary diseases that affects up to 1 in 400 individuals as a consequence of PKD1 or PKD2 genetic defects and lead to renal insufficiency by the fourth to sixth age decade. A recent study shows that c-MYC-induced SIRT1 upregulation is present in an ADPKD murine model [87] in which genetic or pharmacological SIRT1 inhibition suppresses cysts growth, indicating that SIRT1 might induce cyst formation through cell survival mechanisms such as P53 deacetylation and inhibition. Although unusual for SIRT1 to have a protective effect in a normal physiological environment, SIRT1 inhibition might prove effective in a pathological scenario.

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Besides the functions previously described, the kidneys also play a major role in the reninangiotensin system (RAS), given that the justaglomerular cells from kidney afferent arterioles are the major renin production site [88]. RAS peptide cascade regulates metabolism at several key points. Both RAS peptide cascade and sirtuins are modulated by diverse diet composition, suggesting a similar effect from these systems. Those findings led to other studies that confirmed this interaction both in vivo and ex vivo with cultured cells in which the activation or inhibition of RAS/Ang-(17) axis modulates sirtuins expression [89].

3.2.5 Pancreas Both SIRT1 and SIRT4 have been described as playing a major role in pancreatic cells regulation. SIRT1 increases insulin gene transcription and improves glucose-stimulated insulin secretion (GSIS) through UCP2 gene expression reduction [90], given that mice overexpressing SIRT1 showed increased GSIS [91], while also protecting pancreatic β-cells from inflammation-induced apoptosis [92]. Conversely, SIRT4 inhibits GDH-mediated amino acids-induced insulin secretion [93].

3.2.6 Brain The hypothalamus is a major brain region that is fundamental for the control of human physiology. SIRT1 levels in the hypothalamus are affected by diet and seem to mediate many aspects in this structure control [94]. In the absence of SIRT1, the somatotropic axis is inhibited and during caloric restriction SIRT1 levels are increased in both the lateral (LHA) and dorsomedial hypothalamic (DHA) axes. SIRT1 promotes through physical activity an increase in body temperature by supraregulation of orexin receptor 2, which is involved in appetite-regulating feedback mechanisms. In anorexigenic pro-opiomelanocortin (POMC) neurons SIRT1 is key for the diet-induced energy expenditure [95], and SIRT1-KO POMC neurons are more susceptible to obesity development [96]. SIRT1 levels are reduced with aging in the central nervous system (CNS) and, indeed, SIRT1 overexpression can delay the agerelated decay in circadian functions [97], while also delaying aging and prolonging mice life expectancy [98].

3.3 Nutrition as a therapeutic model for sirtuin regulation Metabolic changes are directly related to sirtuin level and activity, thus being able to contribute to obesityrelated comorbidities. Currently, several medicines with a therapeutic approach to treat obesity, such as Orlistat, present serious side effects including increased blood pressure, dry mouth, headache, and insomnia [99]. Sibutramin, a weight control drug, was removed from circulation by the FDA in 2010 because of increased cardiovascular risks. In this sense, there has been observed an increase in the search for alternative and natural antiobesity products. Natural products capable of regulating PPARγ expression, transcriptional activity, and/or sirtuin-mediation have been highlighted as having potential antiadipogenesis action and therefore targets for antiobesity agents [100]. Nowadays, most natural products investigated are phytochemicals obtained from plants used as food and/or medicine, which are both relatively safe and of easy access [100]. Diet-obtained phytochemicals, mainly from fruits and vegetables, may be employed as antiobesity agents given that evidence suggests they may reduce adipose tissue mass, through adipogenesis inhibition, lipolysis stimulation, and apoptosis of existing adipocytes. Diet-obtained phytochemicals include terpenoids, polyphenols, phytosterols and alkaloids, which are amongst the most common components with antiobesity properties [101,102]. Moreover, therapeutic measures have been focused on sirtuin activity modulation through stimulus or inhibition via synthetic or natural active principles (Fig. 3.3), particularly food and supplements. Based on these findings, nutritional studies have focused on the use of food for the modulation of sirtuins, using fruits, vegetables, good red wine, and dark chocolate. Nutritional trends have adopted the “sirtfood diet,” developed by nutritionists Aidan Goggins and Glen Matten, a nutritional method based on the use of diet polyphenols, imitating the effects of caloric restriction, fasting, and exercise. Sirtuins-selecting activators and inhibitors are still in their initial stages, but some natural compounds are already commercially available [103]. The interest for new sirtuin-modulating molecules is based on potential health benefits found in caloric restrictive diets; these not only improve mammal metabolism but also prolong their life expectancy through SIRT1 induction [104], although its role in this regard is still debatable [105]. Fig. 3.3 shows some of the better-known compounds and food that act upon sirtuin modulation to improve the metabolic overall outcome.

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FIGURE 3.3 Natural and synthetic molecules applied on sirtuins metabolic activation or inhibition.

3.3.1 Polyphenols Flavonoids are metabolic polyphenols with pharmacological properties synthesized by plants and fungi, and due to their extensive biological activities, they have been studied for medicine development. Flavonoids have been shown to modulate NAD1-dependent histones deacetylase activity, like SIRT1 (resveratrol, piceatannol, butein, isoliquiritigenin, fisetin, quercetin) [106] and SIRT6 (catechin, luteolin, quercetin, kaempferol, myricetin, delphinidin, cynidin) [107] (Table 3.1). SIRT6 targets lysines 9 (H3K9) and 56 (H3K56) on the H3 sequence and has been shown to efficiently deacetylatethese sites. Those SIRT6 functions are involved in the regulation of several genes, including stress-response. SIRT6-deficient cells presented oxidative stress sensitivity and a reduced DNA repair capability. SIRT6 is also involved in glucose and lipids metabolism, regulating the expression of multiple glycolytic and lipidic genes related to cell response [108,109]. Those SIRT6 functions highlight its importance to aging processes and the protection of many cell functions. Therefore SIRT6-regulating compounds are promising therapeutic targets for age-related diseases, including but not limited to cancer, diabetes, neurodegenerative disorders, and metabolic disturbances [107].

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TABLE 3.1 Polyphenols activity on activation and(or) inhibition of Sirt 1 and Sirt 6. Inhibition (mean) Compound

Sirtuin

10 µM

100 µM

Activation

EC50

References

Butein

1

Na

8.53

Na

Na

[106]

Resveratrol

1

Na

13.4

Na

Na

Piceatannol

1

Na

7.90

Na

Na

Isoliquiritigenin

1

Na

7.57

Na

Na

Fisetin

1

Na

6.58

Na

Na

Quercetin

1

Na

4.59

Na

Na

10 µM(%)

100 µM(%)

(1)-Catechin

6

17.0

26.0

0.8

Na

(2)-Catechin

6

25.0

54.0

0.4

Na

(2)-Gallocatechin

6

17.0

23.0

0.2

Na

(2)-Catechin gallate

6

62.0

88.0

0.1

2.5

(2)-Gallocatechin gallate

6

79.0

84.0

0.01

5.4

(2)-Epicatechin

6

Nd

10.0

Nd

Na

(2)-Epigallocatechin

6

Nd

4.1

Nd

Na

(2)-Epicatechin gallate

6

15.0

60.0

0.1

Na

(2)-Epigallocatechin gallate

6

10.0

42.0

0.8

Na

Naringenin

6

8.3

23.0

1.1

Na

Eriodictoyl

6

19.0

27.0

1.1

Na

Apigenin

6

Nd

1.0

0.9

Na

Luteolin

6

24.0

29.0

1.2

270

Kaempferol

6

40.0

24.0

2.2

Nd

Quercetin

6

27

40.0

1.5

990

Myricetin

6

Nd

0.0

2.3

404

Cyanidin

6

Nd

0.0

2.6

460

Delphinidin

6

Nd

0.0

2.2

760

Genistein

6

1.8

9.6

0.7

Na

Biochanin A

6

13

24.0

Nd

Na

Nicotinamide

6

Na

58.0

Nd

Na

Gallic Acid

6

Na

14.0

1.4

Na

Hydroferulic acid

6

Na

212.0

1.8

Na

p-Coumaric acid

6

Na

8.5

0.6

Na

Caffeic Acid

6

Na

25.9

1.0

Na

trans-Ferulic acid

6

Na

28.6

0.9

Na

Sinapic Acid

6

Na

8.0

0.6

Na

EC50, Half maximal effective concentration; Na, not available; Nd, not determined.

I. Sirtuins and metabolic disease

[107]

47

3.4 Resveratrol

3.4 Resveratrol O-3,5,40 -Trihydroxystilbene, commonly known as resveratrol, is a polyphenol whose molecule contains two phenyl rings separated by a methylene bridge, and was the first compound known to simulate the effects of CR as a sirtuin-stimulator [106,110]. Resveratrol can be found in several foods (Table 3.2), like berries, peanut, red grape, and red wine (0.1 a 14.3 mg/L concentrations), which might help to explain the lower rates of cardiac diseases in France despite its saturated fatrich diet [141143]. Resveratrol can induce CR-like genetic expression TABLE 3.2 Composition of resveratrol in food using the Phenol-explore database [140]. Categories of food

Food

Mean content

Min

Max

SD

n

N

References

Fox grape, red wine

0.25 mg/100 mL

0.01

0.67

0.30

4

4

[111,112]

Alcoholic beverages Wines—Berry wines

Wines—Grape wines

Wines—Sparkling wines

23

Fox grape, white wine

0.01 mg/100 mL

1.00

0.02

0.01

2

2

[112]

Muscadine grape, red wine

3.02 mg/100 mL

1.41

4.41

1.13

5

5

[111]

Wine (red)

0.27 mg/100 mL

0.00

2.78

0.31

478

956

[112122]

23

Wine (rose´)

0.12 mg/100 mL

5.00

0.29

0.08

18

36

[112,113,123,124]

Wine (white)

0.04 mg/100 mL

0.00

0.17

0.03

101

270

[116,118,125,126]

23

23

23

Champagne

9.00

mg/100 mL

8.00

0.01

1.15

4

4

[127]

Chocolate, dark

0.04 mg/100 g FW

0.04

0.04

0.00

1

1

[128]

Bilberry, raw

0.67 mg/100 g FW

0.67

0.67

0.00

1

1

[129]

European cranberry

1.92 mg/100 g FW

1.92

1.92

0.00

1

1

[129]

Grape (black)

0.15 mg/100 g FW

0.02

0.58

0.20

7

7

[121,130]

Grape (green)

0.02 mg/100 g FW

0.00

0.04

0.02

5

5

[121,131]

Lingonberry, raw

3.00 mg/100 g FW

3.00

3.00

0.00

1

1

[129]

Redcurrant, raw

1.57 mg/100 g FW

1.57

1.57

0.00

1

1

[129]

Strawberry, raw

0.35 mg/100 g FW

0.35

0.35

0.00

1

1

[129]

Grape (green), pure juice

5.0823 mg/100 mL

0.00

0.01

2.3123

12

12

[132]

Peanut, butter

0.04 mg/100 g FW

0.01

0.07

0.02

35

35

[133135]

Vinegar

4.5723 mg/100 mL

0.00

0.01

4.08e-03

6

92

[136]

Peanut

0.08 mg/100 g FW

9.0023

1.12

0.28

16

16

[134,137]

0.19

0.08

12

12

[138,139]

2.20

0.17

0.05

11

11

[139]

0.00

0.01

3.49e-03

12

12

[134,135]

0.16

0.05

7

7

[138]

Coffee and cocoa Cocoa—Chocolate

Fruits and fruit products Fruits—Berries

Nonalcoholic beverages Fruit juices—Berry juices

Oils Oils—Nut oils

Seasonings Other seasonings

Seeds Nuts

Peanut, dehulled Peanut, dehulled, roasted Peanut, roasted Pistachio, dehulled

0.07 mg/100 g FW 0.02 mg/100 g FW 23

5.37

mg/100 g FW

0.11 mg/100 g FW

23

3.00

23

23

9.00

FW, Fresh weight; Max, maximum; Min, minimum; n, number of original data points used to calculate the mean content value; N, total number of original individual samples analyzed; SD, standard deviation. Composic¸a˜o de resveratrol em alimento utilizando-se o banco de dados Phenol-explore [140].

I. Sirtuins and metabolic disease

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3. Sirtuins and metabolic regulation: food and supplementation

patterns in many tissues, while also reducing aging signs without affecting any sirtuin gene expression [144,145]. In vivo studies have shown that resveratrol improves the overall health of hypercaloric dietfed mice [59]. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density [145]. Due to its low bioavailability, reworked resveratrol versions with improved bioavailability were developed, with one such formulation containing 150 mg/day resveratrol (resVida) having demonstrated beneficial effects in healthy obese males, lowering liver lipidic content, blood glucose, triglycerides, alanine-aminotransferase, and inflammatory markers, thus emulating CR-diet effects [146]. Moreover, oral resveratrol supplementation acutely improved endothelial-dependent vasodilatation in a dose-related manner, which was correlated with the plasma resveratrol content [147]. Resveratrol administered as Longevinex formulation improved flow-mediated dilation after 3 months of treatment, with the parameter returning to the baseline 3 months after treatment interruption, without affecting blood pressure, insulin resistance, lipid profile, or inflammatory markers [148]. SRT501, another commercial resveratrol formulation, reworked the molecular signature that overlaps with resveratrol, like improved mitochondrial biogenesis, metabolic signaling pathways, and impaired proinflammatory pathways in hypercaloric diet-fed mice. SRT501 generated a genetic profile mirroring that of CR [149]. It has also been demonstrated that those formulations reduced blood glucose and improved insulin sensitivity in Phase II type 2 diabetes patients, highlighting its potential clinical utility [150]. Furthermore, 30 mg/kg/day resveratrol administration for 60 days to HFD-fed mice reduced these animals’ body fat, total cholesterol, triacylglycerol, transaminases, and insulin plasma levels, results that were accompanied by reduced liver TNF-α, IL-6, and NF-κB mRNA levels. Analysis of liver adipogenesis-related genes indicated reduced ACC, PPAR-γ, and SREBP-1 mRNA levels in obese mice treated with the polyphenol through increased SIRT1 expression, resulting in reduced hepatic steatosis [151].

3.5 Gallic acid Gallic acid (3,4,5-trihidroxybenzoic acid) (GA) is a natural polyphenol found in microalgae, some bacteria and vegetables (Table 3.3) [197]. In vivo studies have shown that GA has antiobesity, hypolipidemic and antidiabetogenic effects [198200]. Amongst the many mechanisms through which GA may regulate the metabolic functions is sirtuin modulation. A 9-week 10 mg/kg/day GA treatment of HFD-fed mice improved blood glucose levels and insulin homeostasis, and delayed body weight gain without affecting food intake, results that might be, at least in part, attributed to the AMPK/Sirt1/PGC1α pathways modulation, as confirmed by the SIRT1-KO mice which showed lower expression of mitochondrial function-related genes and reduced PGC1α deacetylated form. Moreover, it also promotes WAT tissue browning through Uncoupling Proteins (UCPs) 1 and 3 [201]. Another study found similar results in standard chow and HFD-fed mice treated for 60 days with 100 mg/kg GA, resulting in SIRT1 increased expression in WAT [202].

3.6 Nonresveratrol related sirtuin activators Given the aforementioned importance of the sirtuins, there has been a great interest in discovering a more potent activator than resveratrol. Milne et al. identified nonresveratrol-related SIRT1 activators with significantly increased action. Amongst those, SRT1720 compound, which shares the same molecular binding and activation site with resveratrol, is the most effective so far, with stimulatory activity at 750% on 10 μM dose with substrate deacetylation both in vitro and in vivo [149]. Furthermore, SIRT1720’s effectiveness was observed for in vivo type 2 diabetes models: genetically obese mice (Lep ob/ob), DIO mice, and fa/fa Zucker rats. SRT1720 to DIO mice not only reduced postprandial blood glucose, partially restored insulin levels, and lowered fast blood glucose, but also improved oxidative metabolism in skeletal muscle, brown adipose tissue, and liver through a global metabolic adaptation that mimics lower energy levels [61,149,203]. Other SRT1720-treatment benefits included lower liver triglycerides and aminotransferases as well as lipogenic genes expression [204]; increased average and maximum life expectancy of HFD-fed mice, increased insulin sensitivity, and normalized the genetic profile for apoptosis and inflammation markers [205]. In a preclinical cancer treatment evaluation, SRT1720 induced apoptosis in vitro in multiple cells myeloma and reduced xenoinserted growth tumor through a mechanism involving the ATM-CHK2/Caspase89 signaling pathway [206].

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3.6 Nonresveratrol related sirtuin activators

TABLE 3.3 Composition of Gallic acid in food using the Phenol-explore database [140]. Categories of food

Food

Mean content

Min

Max

SD

n

N

References

Beer (ale)

0.11 mg/100 mL

0.03

0.18

0.08

3

3

[152,153]

Beer (dark)

0.03 mg/100 mL

0.03

0.03

0.00

1

1

[152,153]

Beer (regular)

0.07 mg/100 mL

0.00

0.70

0.17

25 47

[153158]

Liquors—Nut liquors

Walnut, liquor

15.15 mg/100 mL

11.20

21.70

4.81

4

4

[159]

Spirits—Brandy

Cognac

0.23 mg/100 mL

0.10

0.47

0.19

3

36

[160]

Spirits—Rum

Rum

0.06 mg/100 mL

0.06

0.06

0.00

1

21

[160]

Spirits—Whisky

Scotch whisky

0.09 mg/100 mL

0.05

0.12

0.03

4

66

[160]

Wines—Fortified Wines

Sherry

0.60 mg/100 mL

0.60

0.60

0.00

1

1

[161]

Wines—Grape wines

Wine (red)

3.59 mg/100 mL

0.00

12.60

2.71

99 514 [117,119,162]

Wine (rose´)

1.04 mg/100 mL

0.94

1.43

0.35

2

Wine (white)

0.22 mg/100 mL

0.00

1.10

0.32

22 105 [116,162,164]

Champagne

0.05 mg/100 mL

0.01

0.08

0.03

4

4

[127]

Dried fruits—Dried other fruits

Date, dried

1.56 mg/100 g FW

0.00

3.09

1.55

3

3

[165]

Fruits—Berries

Blackberry, raw

4.67 mg/100 g FW

2.00

9.00

3.79

3

3

[166]

Cloudberry

4.20 mg/100 g FW

4.20

4.20

0.00

1

1

[167]

6.00

0.00

1

1

[168]

Alcoholic beverages Beers

Wines—Sparkling wines

5

[113,163]

Fruits and fruit products

23

23

mg/100 g FW 6.00

23

Fruits—Citrus

Grapefruit

6.00

Fruits—Other fruits

Date, fresh

0.16 mg/100 g FW

0.00

0.48

0.28

3

3

[165]

Fruits—Tropical fruits

Banana, raw

1.00 mg/100 g FW

0.87

1.08

0.12

3

3

[169]

Jams—Pome jams

Quince, jam

0.67 mg/100 g FW

0.00

6.05

1.63

20 20

[170]

Grape (green), pure juice

0.10 mg/100 mL

0.10

0.10

0.00

1

18

[171]

Sea-buckthornberry, pure juice

0.20 mg/100 mL

0.15

0.26

0.08

2

2

[172]

Apple (cider), juice from concentrate 0.04 mg/100 mL

0.00

0.12

0.06

6

6

[173]

Nonalcoholic beverages Fruit juices—Berry juices

Fruit juices—Pome juices

Apple (cider), pure juice

0.18 mg/100 mL

0.14

0.22

0.03

4

4

[173]

Apple (dessert), pure juice

0.66 mg/100 mL

0.00

1.36

0.77

4

4

[174176]

Fruit juices—Tropical fruit juices Pomegranate, pure juice

0.45 mg/100 mL

0.03

3.08

0.86

13 13

[177]

Tea infusions

Tea (black), infusion

4.63 mg/100 mL

0.07

14.58

4.38

39 53

[178181]

Tea (green), infusion

0.49 mg/100 mL

4.0023 3.33

0.89

44 44

[178182]

Tea (oolong), infusion

0.68 mg/100 mL

0.02

3.50

1.20

14 14

[178,179,183]

Common sage, dried

5.25 mg/100 g FW

0.00

10.50

7.42

2

2

[184,185]

Marjoram, dried

1.60 mg/100 g FW

1.60

1.60

0.00

1

1

[186]

Oregano, dried (wild marjoram)

5.15 mg/100 g FW

0.00

10.30

7.28

2

2

[184,185]

Other seasonings

Vinegar

2.59 mg/100 mL

0.00

9.50

2.36

27 187 [136,187,188]

Spices

Cloves

458.19 mg/100 g FW 17.47

Seasonings Herbs

783.50 298.99 5

5

[189191] (Continued)

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3. Sirtuins and metabolic regulation: food and supplementation

TABLE 3.3 (Continued) Categories of food

Food

Mean content

Nuts

Chestnut, raw

Soy and soy products

Min

Max

SD

n

N

References

479.78 mg/100 g FW 276.00 907.00 182.55 9

9

[192]

Soybean, sprout, raw

0.70 mg/100 g FW

0.70

0.70

0.00

1

1

[193]

Cabbages

Cauliflower, raw

0.69 mg/100 g FW

0.68

0.70

0.01

2

2

[193]

Fruit vegetables

Eggplant (purple), whole, raw

0.14 mg/100 g FW

0.11

0.20

0.05

3

3

[194]

Olive (black), raw

0.02 mg/100 g FW

0.01

0.04

0.02

3

3

[195]

Chicory (green), raw

25.84 mg/100 g FW

12.75

38.93

18.51

2

2

[196]

Chicory (red), raw

14.56 mg/100 g FW

7.99

30.94

8.57

6

6

[196]

Seeds

Vegetables

Leaf vegetables

FW, Fresh weight; Max, maximum; Min, minimum; n, number of original data points used to calculate the mean content value; N, total number of original individual samples analyzed; SD, standard deviation. Composic¸a˜o de resveratrol em alimento utilizando-se o banco de dados Phenol-explore [140].

Besides SRT1720, new compounds were identified, like oxazolo [4,5-b] pyridine [207] and imidazo (1,2-b) pyridazine, thiazole derivatives containing oxazolopyridine nuclei with potential new therapeutic targets for treatment of several disturbances. The most potent analog from this series, compound 29, showed significant oral bioavailability in mice and rats in three different models, without affecting body weight, as well as general chemical clinics and hematology [208]. Another recently developed new compound is SRT2104, capable of attenuating inflammation in a dextran sulfate sodium-induced (DSS) colitis model, with a lower colitis score compared to prednisone as well as improving weight loss. SRT2104 has been also tested in a Phase II patient clinical study with individuals suffering from metabolic, inflammatory, and cardiovascular diseases, after it was concluded that it was safe and well-tolerated in Phase I trials with healthy subjects [209]. In addition, pyrrolo [3,2-b] quinoxaline has been described as potent lipolytic agents with in vitro antiinflammatory properties, although its possible effect on animal models remains untested [210]. Other compounds, prepared by Mai et al., are 1,4-dihydropyridine (DHP) derivatives exhibiting a benzyl group in the N1 position, which have been shown to act as potent human SIRT1, SIRT2, and SIRT3 activators, with increased mitochondrial activity and reduced murin C2C12 myoblasts senescence [211]. In conclusion, so far no sirtuin activator has been shown to extend standard diet-fed mice life expectancy, but their effects over general health and age-related diseases might be just as interesting.

3.7 Food and sirtuins 3.7.1 Mediterranean diet Diet is a modifiable environmental factor, being one of the cornerstones for obesity management, which might also modify sirtuins activity as previously described. The Mediterranean diet (MD) is a healthy eating habit based on a diet common in Mediterranean countries [212]. MD is characterized by very low NEFAs ingestion and high intake of polyunsaturated fatty acids (PUFA) and micronutrients, including vitamins and minerals known to improve plasmatic antioxidative capabilities [213]. Moreover, both the quality and quantity of ingested lipids affect lipids and triglycerides stocks in adipose tissue and even other organs, such as the liver [214], resulting in a deleterious effect. A study conduct with obese patients in Naples, Italy showed that adhesion to MD for 7 days was associated with increased SIRT4 levels, lower ectopic fat deposition, and adipocytes dysfunction when compared to patients with lower adhesion to MD, regardless of BMI. Circulating SIRT4 levels varied not only according to energy intake but due to intake of antioxidants-containing foods, such as fruits, olive oil, vegetables, and fish [215]. This positive association between MD and circulating SIRT4 levels suggests that a SIRT4 increase might represent yet another antioxidant metabolic advantage to obese individuals and reinforces the importance of the role of nutrition professionals in multidisciplinary teams for obesity control.

I. Sirtuins and metabolic disease

3.7 Food and sirtuins

51

3.7.2 Berberin Berberin, a commonly used medicine in traditional Chinese medicine, has attracted increasingly more attention for its potential therapeutic qualities on hepatic steatosis, diabetes, and dislipidemia treatment [216]. It has been shown that berberin and its derivatives reduced HepG2 cells hepatic steatosis [217] as well as HFD-fed mice hepatic steatosis [218221]. In a double-blind study, it also reduced NAFLD [222] and serum cholesterol in hypercholesterolemic patients [223]. Although berberin’s beneficial effects seem to be, at least in part, AMPK-mediated [224,225] and LDLR increased expression [223], one of the mechanisms for the hepatocytes’ lipids metabolism improvement is due to SIRT1-mediated autophagy induction and FGF21 expression. Berberin stimulates SIRT1 deacetylation activity and induces autophagy through autophagy-protein 5, while also promoting hepatic gene expression and circulating levels of FGF21 and chthonic bodies in a SIRT1-dependent manner in mice [226].

3.7.3 Green cardamom Green cardamom (GC) (Elettaria cardamomum) is an aromatic plant traditionally used as a culinary ingredient, commonly cultivated in Sri Lanka, Thailand, and Guatemala. It is an important source of flavonoids, alkaloids, terpenoids, anthocyanins, and phenolic compounds [227,228]. GC has been used for the treatment of several disturbances, including asthma, indigestion, and congestive hepatopathy [229], mainly because of its antioxidant, antiinflammatory, antitumor, and antimicrobial activities [230,231]. Furthermore, it can also be used in the treatment of obesity and its associated comorbidities, such as NAFLD; 3 g/day for 3 months GC administration reduced liver fat, reactive C-protein, and antiinflammatory factors through increased SIRT1 in plasma [232]. Those effects might be associated with its active principles: 1,8-cineol [eucaliptol], beta-pinenol, and geraniol, polyphenols and known sirtuin modulators [233235]. The mechanisms for GC’s antiinflammatory effects include reduced inflammatory cells infiltration, lipidic peroxidation, and advanced protein oxidation products (APOP), as well as an increase in antioxidants enzymes [236,237], reduced inflammatory mediators, such as COX-2, iNOS and NF-κB [238240], lower hemolysis by vitamin E deficiency [241], and increased activity of adipogenesis and NBK cells [230].

3.7.4 Cocoa Cocoa (Theobroma cacao) is a flavonoids-rich fruit, with potent antioxidant effects and well-established benefits for cardiovascular health, due to improved endothelial function and reduced cellular neurodegeneration [242,243]. A study using pholyphenol-enriched cocoa evaluated its potential benefits through the sirtuins pathway in a diabetic retinopathy model. It was found that SIRT1 activity was reduced in retinal tissue of diabetic mice, NAD1 intracellular levels were increased, and Lys310-p65 acetylation was increased in the retinal tissue. 0.1222.9 mg/kg/day Cacao administration by Gavage for 16 weeks reduced SIRT1 inhibition and increased NAD1, leading to lLys310-p65 deacetylation, which then regulated GFAP expression in diabetic rats retinal tissue; all those effects allowed for SIRT1-mediated neuroprotection in diabetic retinopathy-presenting tissues [244].

3.7.5 Indole-3-carbinol Indol-3-carbinol (I3C) is a natural product found in cabbage and broccoli with chemotherapeutic properties, including antiproliferative and proapoptotic properties against several types of cancer [245]. In vitro, I3C targets a wide array of cell cycle and survival-related signaling pathways, such as AKT, NF-κB, leukemia/lymphoma B2 cells, mitogen-activated kinases, cyclin-dependent kinases, and cyclin D1 [246]. Recently, I3C has been highlighted as a possible antiobesity agent, being able to reduce blood glucose and insulin in HDF-fed mice [247] as well as reducing inflammatory cytokines such as IL-6 expression in adipocytes and macrophage [248]. In vivo it was shown that 100 mg/kg/day I3C administration reduced body weight and visceral fat weight gain in HFD-fed mice [249]. I3C binds to SIRT1 and activates 3T3-L1 cell deacetylation and reduced adipogenic C/EBPα, PPARγ2, FAS, and aP2 mRNA levels in 3T3-L1 cells but not in SIRT1 knockdown cells, thus it was concluded that I3C specifically inhibits adipocytes differentiation through SIRT1 binding and activity regulation, suggesting an important route to SIRT1-direct drugs [250].

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3. Sirtuins and metabolic regulation: food and supplementation

3.7.6 Xanthigen Xanthigen is a source of punic acid and fucoxantin, derivatives from pomegranate seed oil and brown seaweed, respectively, both with antitumor, antioxidant, and antiinflammatory properties [100,251]. A study found that xanthigen interfered with adipocytes suppression, as seen on 3T3-L1 pre-adipocytes. Also, Western blot analysis showed increased SIRT levels, indicating that xanthigen is somehow involved in the suppression of adipocytes differentiation through C/EBPβ, C/EBPδ, and PPARγ inhibition coupled to SIRT1 pathway stimulation and FOXOs and AMPK signaling pathways modulation [252].

3.8 Conclusion In conclusion, we observed that sirtuins are enzymes with great relevance as potential therapeutic targets for improvements in life quality, life expectancy, metabolic disorders, and age-related diseases, given their capability of acting as metabolism modulators. The use of sirtuins activators, as functional diet supplements or even as medicine, has proven to be an effective strategy in the amelioration of obesity-related comorbidities and metabolic syndrome.

References [1] Mendonc¸a CP, Anjos LAd. Aspectos das pra´ticas alimentares e da atividade fı´sica como determinantes do crescimento do sobrepeso/ obesidade no Brasil. Cad de Sau´de Pu´blica 2004;20:698709. [2] Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 19802013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:76681. [3] Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:141528. [4] Aucott LS. Influences of weight loss on long-term diabetes outcomes: symposium on ‘diet and diabetes’. Proc Nutr Soc 2008;67:549. [5] Catenacci VA, Hill JO, Wyatt HR. The obesity epidemic. Clchest Med 2009;30:41544. [6] Faust IM, Johnson PR, Stern JS, Hirsch J. Diet-induced adipocyte number increase in adult rats: a new model of obesity. Am J PhysiolEndocrinol Metab 1978;235:E279. [7] Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 2008;9:367. [8] Boden G. Obesity and free fatty acids. Endocrinol Metab Clin North Am 2008;37:63546. [9] Jung UJ, Choi M-S. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014;15:6184223. [10] Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-κB pathway in rat liver. Diabetes 2005;54:345865. [11] Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006;126:94154. [12] Porcu M, Chiarugi A. The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension. Trends Pharmacol Sci 2005;26:94103. [13] Moniot S, Weyand M, Steegborn C. Structures, substrates, and regulators of mammalian sirtuins opportunities and challenges for drug development. Front Pharmacol 2012;3(16):15p. Available from: https://doi.org/10.3389/fphar.2012.00016. [14] Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J 2007;404:113. [15] McGuinness D, McGuinness DH, McCaul JA, Shiels PG. Sirtuins, bioageing, and cancer. J Aging Res 2011;2011:235754. [16] Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403:795800. [17] Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, et al. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev 2012;92:1479514. [18] Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 2014;25:13845. [19] Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434:11318. [20] Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, et al. A fasting inducible switch modulates gluconeogenesis via activator/ coactivator exchange. Nature 2008;456:26973. [21] Noriega LG, Feige JN, Canto C, Yamamoto H, Yu J, Herman MA, et al. CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability. EMBO Rep 2011;12:106976. [22] Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell 2007;28:91106. [23] Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 2010;285:3395970. [24] Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, et al. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 2009;10:392404.

I. Sirtuins and metabolic disease

References

53

[25] Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 2008;283:2001526. [26] Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 2008;283:2762835. [27] Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A 2007;104:128616. [28] Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, Deng CX. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest 2011;121:447790. [29] Erion DM, Yonemitsu S, Nie Y, Nagai Y, Gillum MP, Hsiao JJ, et al. SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proc Natl Acad Sci U S A 2009;106:1128893. [30] You M, Cao Q, Liang X, Ajmo JM, Ness GC. Mammalian sirtuin 1 is involved in the protective action of dietary saturated fat against alcoholic fatty liver in mice. J Nutr 2008;138:497501. [31] Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 2009;9:32738. [32] Wang RH, Li C, Deng CX. Liver steatosis and increased ChREBP expression in mice carrying a liver specific SIRT1 null mutation under a normal feeding condition. Int J Biol Sci 2010;6:68290. [33] Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, Alt FW, et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 2008;22:17537. [34] Li Y, Xu S, Giles A, Nakamura K, Lee JW, Hou X, et al. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J 2011;25:166479. [35] Gao Z, Zhang J, Kheterpal I, Kennedy N, Davis RJ, Ye J. Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. J Biol Chem 2011;286:2222734. [36] Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010;464:1215. [37] Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, et al. SIRT3 deacetylates mitochondrial 3-hydroxy3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 2010;12:65461. [38] Kendrick AA, Choudhury M, Rahman SM, McCurdy CE, Friederich M, Van Hove JL, et al. Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem J 2011;433:50514. [39] Osborne B, Cooney GJ, Turner N. Are sirtuin deacylase enzymes important modulators of mitochondrial energy metabolism? Biochim Biophys Acta 2014;1840:1295302. [40] Choudhury M, Jonscher KR, Friedman JE. Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat. Aging (Albany NY) 2011;3:1758. [41] He J, Hu B, Shi X, Weidert ER, Lu P, Xu M, et al. Activation of the aryl hydrocarbon receptor sensitizes mice to nonalcoholic steatohepatitis by deactivating mitochondrial sirtuin deacetylase Sirt3. Mol Cell Biol 2013;33:204755. [42] Nassir F, Ibdah JA. Sirtuins and nonalcoholic fatty liver disease. World J Gastroenterol 2016;22:1008492. [43] Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 2010;285:319952002. [44] Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 2013;50:68698. [45] Kim HS, Xiao C, Wang RH, Lahusen T, Xu X, Vassilopoulos A, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab 2010;12:22436. [46] Dominy Jr. JE, Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol Cell 2012;48:90013. [47] Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J Biol Chem 2006;281:3991524. [48] Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004;429:7716. [49] Chalkiadaki A, Guarente L. High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab 2012;16:1808. [50] Guarente L. Calorie restriction and sirtuins revisited. Genes Dev 2013;27:207285. [51] Jing E, Gesta S, Kahn CR. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab 2007;6:10514. [52] Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Ppargamma. Cell 2012;150:62032. [53] Gillum MP, Kotas ME, Erion DM, Kursawe R, Chatterjee P, Nead KT, et al. SirT1 regulates adipose tissue inflammation. Diabetes 2011;60:323545. [54] Wang H, Qiang L, Farmer SR. Identification of a domain within peroxisome proliferator-activated receptor gamma regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol 2008; 28:188200. [55] Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 2008;8:33341. [56] Wang F, Tong Q. SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1 repressive interaction with PPARgamma. Mol Biol Cell 2009;20:8018. [57] Wang F, Nguyen M, Qin FX, Tong Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 2007;6:50514. [58] Kanfi Y, Peshti V, Gil R, Naiman S, Nahum L, Levin E, et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 2010;9:16273.

I. Sirtuins and metabolic disease

54

3. Sirtuins and metabolic regulation: food and supplementation

[59] Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006;444:33742. [60] Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006;127:110922. [61] Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab 2008;8:34758. [62] Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005;310:31417. [63] Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007;4:e76. [64] Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 2007;104:1485560. [65] Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 2007;26:191323. [66] Hariharan N, Maejima Y, Nakae J, Paik J, Depinho RA, Sadoshima J. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res 2010;107:147082. [67] Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 2010;11:21319. [68] Schenk S, McCurdy CE, Philp A, Chen MZ, Holliday MJ, Bandyopadhyay GK, et al. Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J Clin Invest 2011;121:42818. [69] Hsu CP, Zhai P, Yamamoto T, Maejima Y, Matsushima S, Hariharan N, et al. Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation 2010;122:217082. [70] Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa S, et al. Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J Biol Chem 2010;285:837582. [71] Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 2007;100:151221. [72] Planavila A, Iglesias R, Giralt M, Villarroya F. Sirt1 acts in association with PPARalpha to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. Cardiovasc Res 2011;90:27684. [73] Oka S, Alcendor R, Zhai P, Park JY, Shao D, Cho J, et al. PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab 2011;14:598611. [74] Shinmura K, Tamaki K, Bolli R. Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxidedependent increase in nuclear Sirt1. Am J Physiol Heart Circ Physiol 2008;295:H234855. [75] Sundaresan NR, Vasudevan P, Zhong L, Kim G, Samant S, Parekh V, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med 2012;18:164350. [76] Karamanlidis G, Lee CF, Garcia-Menendez L, Kolwicz Jr. SC, Suthammarak W, Gong G, et al. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab 2013;18:23950. [77] Pillai VB, Sundaresan NR, Jeevanandam V, Gupta MP. Mitochondrial SIRT3 and heart disease. Cardiovasc Res 2010;88:2506. [78] Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, et al. Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression. Biochem Biophys Res Commun 2008;372:516. [79] Funk JA, Odejinmi S, Schnellmann RG. SRT1720 induces mitochondrial biogenesis and rescues mitochondrial function after oxidant injury in renal proximal tubule cells. J Pharmacol Exp Ther 2010;333:593601. [80] Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, et al. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem 2010;285:1304556. [81] He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, et al. Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Invest 2010;120:105668. [82] Fan H, Yang HC, You L, Wang YY, He WJ, Hao CM. The histone deacetylase, SIRT1, contributes to the resistance of young mice to ischemia/reperfusion-induced acute kidney injury. Kidney Int 2013;83:40413. [83] Simic P, Williams EO, Bell EL, Gong JJ, Bonkowski M, Guarente L. SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep 2013;3:117586. [84] Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K, Araki S, et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest 2010;120:104355. [85] Kitada M, Takeda A, Nagai T, Ito H, Kanasaki K, Koya D. Dietary restriction ameliorates diabetic nephropathy through antiinflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes. Exp Diabetes Res 2011;2011:908185. [86] Hasegawa K, Wakino S, Simic P, Sakamaki Y, Minakuchi H, Fujimura K, et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med 2013;19:1496504. [87] Zhou X, Fan LX, Sweeney Jr. WE, Denu JM, Avner ED, Li X. Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J Clin Invest 2013;123:308498. [88] Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1-7). Physiol Rev 2018;98:50553. [89] de Pinho L, Andrade JMO, Paraı´so A, Filho ABM, Feltenberger JD, Guimaraes ALS, et al. Caldeira AnP, de Carvalho Botelho AC, Campagnole-Santos MJ: diet composition modulates expression of sirtuins and renin-angiotensin system components in adipose tissue. Obesity 2013;21:18305. [90] Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 2006;4:e31.

I. Sirtuins and metabolic disease

References

55

[91] Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Meneur C, et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab 2005;2:10517. [92] Lee JH, Song MY, Song EK, Kim EK, Moon WS, Han MK, et al. Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes 2009;58:34451. [93] Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ, Castronovo V, et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem 2007;282:3358392. [94] Ramadori G, Lee CE, Bookout AL, Lee S, Williams KW, Anderson J, et al. Brain SIRT1: anatomical distribution and regulation by energy availability. J Neurosci 2008;28:998996. [95] Satoh A, Brace CS, Ben-Josef G, West T, Wozniak DF, Holtzman DM, et al. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J Neurosci 2010;30:1022032. [96] Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA, Mostoslavsky R, et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 2010;12:7887. [97] Chang HC, Guarente L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 2013;153:144860. [98] Satoh A, Brace CS, Rensing N, Cliften P, Wozniak DF, Herzog ED, et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab 2013;18:41630. [99] Yun JW. Possible anti-obesity therapeutics from nature—a review. Phytochemistry 2010;71:162541. [100] Feng S, Reuss L, Wang Y. Potential of natural products in the inhibition of adipogenesis through regulation of PPARγ expression and/or its transcriptional activity. Molecules 2016;21:1278. [101] Gonzalez-Castejon M, Rodriguez-Casado A. Dietary phytochemicals and their potential effects on obesity: a review. Pharmacol Res 2011;64:43855. [102] Andersen C, Rayalam S, Della-Fera MA, Baile CA. Phytochemicals and adipogenesis. Biofactors 2010;36:41522. [103] Villalba JM, Alcain FJ. Sirtuin activators and inhibitors. Biofactors 2012;38:34959. [104] Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305:3902. [105] Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvari M, Piper MD, et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011;477:4825. [106] Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425:1916. [107] Rahnasto-Rilla M, Tyni J, Huovinen M, Jarho E, Kulikowicz T, Ravichandran SA, et al. Natural polyphenols as sirtuin 6 modulators. Sci Rep 2018;8:4163. [108] Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010;140:28093. [109] Sebastian C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 2012;151:118599. [110] Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004;430:6869. [111] Lamikanra O, Grimm CC, Rodin JB, Inyang ID. Hydroxylated stilbenes in selected American wines. J Agric Food Chem 1996;44:111115. [112] Sato M, Suzuki Y, Okuda T, Yokotsuka K. Contents of resveratrol, piceid, and their isomers in commercially available wines made from grapes cultivated in Japan. Biosci Biotechnol Biochem 1997;61:18005. [113] Francesca N, Romano R, Sannino C, Le Grottaglie L, Settanni L, Moschetti G. Evolution of microbiological and chemical parameters during red wine making with extended post-fermentation maceration. Int J Food Microbiol 2014;171:8493. [114] Figueiredo-Gonzalez M, Regueiro J, Cancho-Grande B, Simal-Gandara J. Garnacha Tintorera-based sweet wines: detailed phenolic composition by HPLC/DAD-ESI/MS analysis. Food Chem 2014;143:28292. [115] Rodriguez-Delgado MA, Malovana S, Perez JP, Borges T, Garcia Montelongo FJ. Separation of phenolic compounds by highperformance liquid chromatography with absorbance and fluorimetric detection. J Chromatogr A 2001;912:24957. [116] Ribeiro de Lima MT, Waffo-Teguo P, Teissedre PL, Pujolas A, Vercauteren J, Cabanis JC, et al. Determination of stilbenes (trans-astringin, cis- and trans-piceid, and cis- and trans-resveratrol) in Portuguese wines. J Agric Food Chem 1999;47:266670. [117] Burns J, Gardner PT, O’Neil J, Crawford S, Morecroft I, McPhail DB, et al. Relationship among antioxidant activity, vasodilation capacity, and phenolic content of red wines. J Agric Food Chem 2000;48:22030. [118] Gortzi O, Metaxa X, Mantanis G, Lalas S. Effect of artificial ageing using different wood chips on the antioxidant activity, resveratrol and catechin concentration, sensory properties and colour of two Greek red wines. Food Chem 2013;141:288795. [119] Gambelli L, Santaroni G. Polyphenols content in some Italian red wines of different geographical origins. J Food Compos Anal 2004;17:61318. [120] Kallithraka S, Arvanitoyannis I, El-Zajouli A, Kefalas P. The application of an improved method for trans-resveratrol to determine the origin of Greek red wines. Food Chem 2001;75:35563. ˇ [121] Kolouchova´-Hanzlı´kova´ I, Melzoch K, Filip Vr, Smidrkal J. Rapid method for resveratrol determination by HPLC with electrochemical and UV detections in wines. Food Chem 2004;87:1518. [122] Souto AA, Carneiro MC, Seferin M, Senna MJ, Conz A, Gobbi K. Determination of trans-resveratrol concentrations in Brazilian red wines by HPLC. J Food Compos Anal 2001;14:4415. [123] Romero-Pe´rez AI, Lamuela-Ravento´s RM, Waterhouse AL, De La Torre-Boronat M. Levels of cis-and trans-resveratrol and their glucosides in white and rose Vitis vinifera wines from Spain. J Agric Food Chem 1996;44:21248. [124] Abril M, Negueruela A, Pe´rez C, Juan T, Estopan˜a´n G. Preliminary study of resveratrol content in Arago´n red and rose´ wines. Food Chem 2005;92:72936.

I. Sirtuins and metabolic disease

56

3. Sirtuins and metabolic regulation: food and supplementation

[125] Vitrac X, Monti J-P, Vercauteren J, Deffieux G, Me´rillon J-M. Direct liquid chromatographic analysis of resveratrol derivatives and flavanonols in wines with absorbance and fluorescence detection. Analytica Chim Acta 2002;458:10310. [126] Minussi RC, Rossi M, Bologna L, Cordi Lv, Rotilio D, Pastore GM, et al. Phenolic compounds and total antioxidant potential of commercial wines. Food Chem 2003;82:40916. [127] Chamkha M, Cathala B, Cheynier V, Douillard R. Phenolic composition of champagnes from Chardonnay and Pinot Noir vintages. J Agric Food Chem 2003;51:317984. [128] Counet C, Callemien D, Collin S. Chocolate and cocoa: new sources of trans-resveratrol and trans-piceid. Food Chem 2006;98:64957. [129] Ehala S, Vaher M, Kaljurand M. Characterization of phenolic profiles of Northern European berries by capillary electrophoresis and determination of their antioxidant activity. J Agric Food Chem 2005;53:648490. [130] Bavaresco L, Fregoni M, Trevisan M, Mattivi F, Vrhovsek U, Falchetti R. The occurrence of the stilbene piceatannol in grapes. J. Grapevine Res. 2002;41(3):1336. [131] Verzera A, Tripodi G, Dima G, Condurso C, Scacco A, Cincotta F, et al. Leaf removal and wine composition of Vitis vinifera L. cv. Nero d’Avola: the volatile aroma constituents. J Sci Food Agric 2016;96:1509. [132] Romero-Perez AI, Ibern-Gomez M, Lamuela-Raventos RM, de La Torre-Boronat MC. Piceid, the major resveratrol derivative in grape juices. J Agric Food Chem 1999;47:15336. [133] Ibern-Gomez M, Roig-Perez S, Lamuela-Raventos RM, de la Torre-Boronat MC. Resveratrol and piceid levels in natural and blended peanut butters. J Agric Food Chem 2000;48:63524. [134] Lee S, Lee S, Kim M, Chun J, Cheong Y, Lee J. Analysis of trans-resveratrol in peanuts and peanut butters consumed in Korea. Food Res Int 2004;37:24751. [135] Sobolev VS, Cole RJ. Trans-resveratrol content in commercial peanuts and peanut products. J Agric Food Chem 1999;47:14359. [136] Garcı´a-Parrilla MC, Gonza´lez GA, Heredia FJ, Troncoso AM. Differentiation of wine vinegars based on phenolic composition. J Agric Food Chem 1997;45:348792. [137] Chukwumah YC, Walker LT, Verghese M, Bokanga M, Ogutu S, Alphonse K. Comparison of extraction methods for the quantification of selected phytochemicals in peanuts (Arachis hypogaea). J Agric Food Chem 2007;55:28590. ¨, U ¨ nal MK, Yemi¸s F. Determination of the phytoalexin resveratrol (3, 5, 40 -trihydroxystilbene) in peanuts and pistachios by [138] Toku¸soǧlu O high-performance liquid chromatographic diode array (HPLC-DAD) and gas chromatography 2 mass spectrometry (GC-MS). J Agric Food Chem 2005;53:50039. [139] Sanders TH, McMichael RW, Hendrix KW. Occurrence of resveratrol in edible peanuts. J Agric Food Chem 2000;48:12436. [140] Rothwell JA, Perez-Jimenez J, Neveu V, Medina-Remo´n A, M’Hiri N, Garcı´a-Lobato P, et al. Phenol-Explorer 3.0: a major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content. Database (Oxford) 2013;2013:18. Available from: https://doi.org/10.1093/database/bat070. [141] Shukla Y, Singh R. Resveratrol and cellular mechanisms of cancer prevention. Ann N Y Acad Sci 2011;1215:18. [142] Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992;339:15236. [143] Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the ‘French paradox’? Eur J Endocrinol 1998;138:61920. [144] Barger JL, Kayo T, Pugh TD, Prolla TA, Weindruch R. Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Exp Gerontol 2008;43:85966. [145] Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008;8:15768. [146] Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011;14:61222. [147] Wong RH, Howe PR, Buckley JD, Coates AM, Kunz I, Berry NM. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis 2011;21:8516. [148] Fujitaka K, Otani H, Jo F, Jo H, Nomura E, Iwasaki M, et al. Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Nutr Res 2011;31:8427. [149] Smith JJ, Kenney RD, Gagne DJ, Frushour BP, Ladd W, Galonek HL, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol 2009;3:31. [150] Howells LM, Berry DP, Elliott PJ, Jacobson EW, Hoffmann E, Hegarty B, et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res (Phila) 2011;4:141925. [151] Andrade JM, Paraiso AF, de Oliveira MV, Martins AM, Neto JF, Guimaraes AL, et al. Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition 2014;30:91519. [152] Londesborough J, Dresel M, Gibson B, Juvonen R, Holopainen U, Mikkelson A, et al. Analysis of beers from an 1840s’ shipwreck. J Agric Food Chem 2015;63:252536. [153] McMurrough I, Roche G, Cleary K. Phenolic acids in beers and worts. J Inst Brew 1984;90:1817. [154] Jandera P, Skeifikova V, Rehova L, Hajek T, Baldrianova L, Skopova G, et al. RP-HPLC analysis of phenolic compounds and flavonoids in beverages and plant extracts using a CoulArray detector. J Sep Sci 2005;28:100522. [155] Pai TV, Sawant SY, Ghatak AA, Chaturvedi PA, Gupte AM, Desai NS. Characterization of Indian beers: chemical composition and antioxidant potential. J Food Sci Technol 2015;52:141423. [156] Floridi S, Montanari L, Marconi O, Fantozzi P. Determination of free phenolic acids in wort and beer by coulometric array detection. J Agric Food Chem 2003;51:154854. [157] Miedl M, Garcia MA, Bamforth CW. Haze formation in model beer systems. J Agric Food Chem 2005;53:101615. ˇ r´ıkova´ V, Jandera P. Optimisation of gradient HPLC analysis of phenolic compounds and flavonoids in beer using a ˇ ´ L, Skeˇ [158] Rehova CoulArray detector. J Sep Sci 2004;27:134559. [159] Jakopic J, Colaric M, Veberic R, Hudina M, Solar A, Stampar F. How much do cultivar and preparation time influence on phenolics content in walnut liqueur? Food Chem 2007;104:1005.

I. Sirtuins and metabolic disease

References

57

[160] Goldberg DM, Hoffman B, Yang J, Soleas GJ. Phenolic constituents, furans, and total antioxidant status of distilled spirits. J Agric Food Chem 1999;47:397885. [161] Baron R, Mayen M, Merida J, Medina M. Changes in phenolic compounds and browning during biological aging of sherry-type wine. J Agric Food Chem 1997;45:16825. [162] Frankel EN, Waterhouse AL, Teissedre PL. Principal phenolic phytochemicals in selected California wines and their antioxidant activity in inhibiting oxidation of human low-density lipoproteins. J Agric Food Chem 1995;43:8904. [163] Mattila P, Kumpulainen J. Determination of free and total phenolic acids in plant-derived foods by HPLC with diode-array detection. J Agric Food Chem 2002;50:36607. [164] Li P, Wang X, Wang H, Wu Y-N. High performance liquid chromatographic determination of phenolic acids in fruits and vegetables. Biomed Environ Sci: BES 1993;6:38998. [165] Al-Farsi M, Alasalvar C, Morris A, Baron M, Shahidi F. Comparison of antioxidant activity, anthocyanins, carotenoids, and phenolics of three native fresh and sun-dried date (Phoenix dactylifera L.) varieties grown in Oman. J Agric Food Chem 2005;53:75929. [166] Wada L, Ou B. Antioxidant activity and phenolic content of Oregon caneberries. J Agric Food Chem 2002;50:3495500. [167] Maatta-Riihinen KR, Kamal-Eldin A, Torronen AR. Identification and quantification of phenolic compounds in berries of Fragaria and Rubus species (family Rosaceae). J Agric Food Chem 2004;52:617887. [168] Gorinstein S, Cvikrova M, Machackova I, Haruenkit R, Park Y-S, Jung S-T, et al. Characterization of antioxidant compounds in Jaffa sweeties and white grapefruits. Food Chem 2004;84:50310. ´ , Rodrı´guez-Rodrı´guez EM, Romero CD. Content of free phenolic compounds in [169] Me´ndez CdMV, Forster MP, Rodrı´guez-Delgado MA bananas from Tenerife (Canary Islands) and Ecuador. Eur Food Res Technol 2003;217:28790. [170] Silva BM, Andrade PB, Mendes GC, Valentao P, Seabra RM, Ferreira MA. Analysis of phenolic compounds in the evaluation of commercial quince jam authenticity. J Agric Food Chem 2000;48:28537. [171] Bete´s-Saura C, Andre´s-Lacueva C, Lamuela-Ravento´s RM. Phenolics in white free run juices and wines from Penede`s by highperformance liquid chromatography: changes during vinification. J Agric Food Chem 1996;44:30406. [172] Rosch D, Bergmann M, Knorr D, Kroh LW. Structure-antioxidant efficiency relationships of phenolic compounds and their contribution to the antioxidant activity of sea buckthorn juice. J Agric Food Chem 2003;51:42339. [173] Kermasha S, Goetghebeur M, Dumont J, Couture R. Analyses of phenolic and furfural compounds in concentrated and nonconcentrated apple juices. Food Res Int 1995;28:24552. [174] Go¨kmen V, Acar J, Kahraman N. Influence of conventional clarification and ultrafiltration on the phenolic composition of golden delicious apple juice. J Food Qual 2003;26:25766. ˘ E. Effects of various clarification treatments on patulin, phenolic compound and [175] Go¨kmen V, Art k N, Acar J, Kahraman N, Poyrazoglu organic acid compositions of apple juice. Eur Food Res Technol 2001;213:1949. [176] Proteggente AR, Pannala AS, Paganga G, Van Buren L, Wagner E, Wiseman S, et al. The antioxidant activity of regularly consumed fruit and vegetables reflects their phenolic and vitamin C composition. Free Radic Res 2002;36:21733. ˘ E, Go¨kmen V, Artιk N. Organic acids and phenolic compounds in pomegranates (Punica granatum L.) grown in Turkey. [177] Poyrazoglu J Food Compos Anal 2002;15:56775. [178] Kuhr S, Engelhardt UH. Determination of flavanols, theogallin, gallic acid and caffeine in tea using HPLC. Z fu¨r LebensmittelUntersuchung und Forsch 1991;192:5269. [179] Lin J-K, Lin C-L, Liang Y-C, Lin-Shiau S-Y, Juan I-M. Survey of catechins, gallic acid, and methylxanthines in green, oolong, pu-erh, and black teas. J Agric Food Chem 1998;46:363542. [180] Pelillo M, Biguzzi B, Bendini A, Toschi TG, Vanzini M, Lercker G. Preliminary investigation into development of HPLC with UV and MS-electrospray detection for the analysis of tea catechins. Food Chem 2002;78:36974. [181] Stewart AJ, Mullen W, Crozier A. On-line high-performance liquid chromatography analysis of the antioxidant activity of phenolic compounds in green and black tea. Mol Nutr Food Res 2005;49:5260. [182] Wang H, Helliwell K, You X. Isocratic elution system for the determination of catechins, caffeine and gallic acid in green tea using HPLC. Food Chem 2000;68:11521. [183] Kilmartin PA, Hsu CF. Characterisation of polyphenols in green, oolong, and black teas, and in coffee, using cyclic voltammetry. Food Chem 2003;82:50112. [184] Kivilompolo M, Hyotylainen T. Comprehensive two-dimensional liquid chromatography in analysis of Lamiaceae herbs: characterisation and quantification of antioxidant phenolic acids. J Chromatogr A 2007;1145:15564. [185] Kivilompolo M, Oburka V, Hyotylainen T. Comparison of GC-MS and LC-MS methods for the analysis of antioxidant phenolic acids in herbs. Anal Bioanal Chem 2007;388:8817. [186] Proestos C, Komaitis M. Ultrasonically assisted extraction of phenolic compounds from aromatic plants: comparison with conventional extraction technics. J Food Qual 2006;29:56782. [187] Alonso AM, Castro R, Rodr guez MC, Guille´n DA, Barroso CG. Study of the antioxidant power of brandies and vinegars derived from Sherry wines and correlation with their content in polyphenols. Food Res Int 2004;37:71521. [188] Natera R, Castro R, de Valme Garcia-Moreno M, Hernandez MJ, Garcia-Barroso C. Chemometric studies of vinegars from different raw materials and processes of production. J Agric Food Chem 2003;51:334551. [189] Variyar PS. Effect of gamma-irradiation on the phenolic acids of some Indian spices. Int J Food Sci Technol 1998;33:5337. [190] Pathak S, Niranjan K, Padh H, Rajani M. TLC densitometric method for the quantification of eugenol and gallic acid in clove. Chromatographia 2004;60:2414. [191] Shan B, Cai YZ, Sun M, Corke H. Antioxidant capacity of 26 spice extracts and characterization of their phenolic constituents. J Agric Food Chem 2005;53:774959. [192] Do Carmo Barbosa Mendes De Vasconcelos M, Bennett RN, Rosa EA, Ferreira, Cardoso JV. Primary and secondary metabolite composition of kernels from three cultivars of Portuguese chestnut (Castanea sativa Mill.) at different stages of industrial transformation. J Agric Food Chem 2007;55:350816.

I. Sirtuins and metabolic disease

58

3. Sirtuins and metabolic regulation: food and supplementation

[193] Haghi G, Hatami A. Simultaneous quantification of flavonoids and phenolic acids in plant materials by a newly developed isocratic high-performance liquid chromatography approach. J Agric Food Chem 2010;58:1081216. [194] Kowalski R, Kowalska G. Phenolic acid contents in fruits of aubergine (Solanum melongena L.). Pol J Food Nutr Sci 2005;14:3741. [195] Bianco A, Buiarelli F, Cartoni G, Coccioli F, Jasionowska R, Margherita P. Analysis by liquid chromatography-tandem mass spectrometry of biophenolic compounds in olives and vegetation waters, Part I. J Sep Sci 2003;26:40916. [196] Rossetto M, Lante A, Vanzani P, Spettoli P, Scarpa M, Rigo A. Red chicories as potent scavengers of highly reactive radicals: a study on their phenolic composition and peroxyl radical trapping capacity and efficiency. J Agric Food Chem 2005;53:816975. [197] Ow YY, Stupans I. Gallic acid and gallic acid derivatives: effects on drug metabolizing enzymes. Curr Drug Metab 2003;4:2418. [198] Punithavathi VR, Stanely Mainzen Prince P, Kumar MR, Selvakumari CJ. Protective effects of gallic acid on hepatic lipid peroxide metabolism, glycoprotein components and lipids in streptozotocin-induced type II diabetic Wistar rats. J Biochem Mol Toxicol 2011;25:6876. [199] Jang A, Srinivasan P, Lee NY, Song HP, Lee JW, Lee M, et al. Comparison of hypolipidemic activity of synthetic gallic acid-linoleic acid ester with mixture of gallic acid and linoleic acid, gallic acid, and linoleic acid on high-fat diet induced obesity in C57BL/6 Cr Slc mice. Chem Biol Interact 2008;174:10917. [200] Hsu CL, Yen GC. Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats. Br J Nutr 2007;98:72735. [201] Doan KV, Ko CM, Kinyua AW, Yang DJ, Choi Y-H, Oh IY, et al. Gallic acid regulates body weight and glucose homeostasis through AMPK activation. Endocrinology 2015;156:15768. [202] Paraiso AF, Sousa JN, Andrade JMO, Mangabeira ES, Lelis DF, de Paula AMB, et al. Oral gallic acid improves metabolic profile by modulating SIRT1 expression in obese mice brown adipose tissue: a molecular and bioinformatic approach. Life Sci 2019;237:116914. [203] Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007;450:71216. [204] Yamazaki Y, Usui I, Kanatani Y, Matsuya Y, Tsuneyama K, Fujisaka S, et al. Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice. Am J Physiol Endocrinol Metab 2009;297:E117986. [205] Minor R, Baur J, Gomes A, Ward T, Csiszar A, Mercken EM, et al. SRT1720 improves survival and healthspan of obese mice. Sci Rep 2011;1:70:111. Available from: https://doi.org/10.1038/srep00070. [206] Chauhan D, Bandi M, Singh AV, Ray A, Raje N, Richardson P, et al. Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells. Br J Haematol 2011;155:58898. [207] Bemis JE, Vu CB, Xie R, Nunes JJ, Ng PY, Disch JS, et al. Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators. Bioorg Med Chem Lett 2009;19:23503. [208] Vu CB, Bemis JE, Disch JS, Ng PY, Nunes JJ, Milne JC, et al. Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators. J Med Chem 2009;52:127583. [209] van der Meer A, Scicluna B, Lin J, Jacobson E, Vlasuk G, van der Poll T. The first demonstration of clinical activity by a small molecule sirt1 activator: srt2104 reduces cytokine release and coagulation activation in a human endotoxemia model. In: Inflammation research. Basel: Birkhauser Verlag AG; 2011. p. 82. [210] Nayagam VM, Wang X, Tan YC, Poulsen A, Goh KC, Ng T, et al. SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. J Biomol Screen 2006;11:95967. [211] Mai A, Valente S, Meade S, Carafa V, Tardugno M, Nebbioso A, et al. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J Med Chem 2009;52:5496504. [212] Martinez-Gonzalez MA, Salas-Salvado J, Estruch R, Corella D, Fito M, Ros E. Benefits of the Mediterranean diet: insights from the PREDIMED study. Prog Cardiovasc Dis 2015;58:5060. [213] Scoditti E, Capurso C, Capurso A, Massaro M. Vascular effects of the Mediterranean diet-part II: role of omega-3 fatty acids and olive oil polyphenols. Vasc Pharmacol 2014;63:12734. [214] Papackova Z, Cahova M. Fatty acid signaling: the new function of intracellular lipases. Int J Mol Sci 2015;16:383155. [215] Barrea L, Tarantino G, Somma CD, Muscogiuri G, Macchia PE, Falco A, et al. Adherence to the Mediterranean diet and circulating levels of Sirtuin 4 in obese patients: a novel association. Oxid Med Cell Longev 2017;2017:6101254. [216] Yin J, Zhang H, Ye J. Traditional chinese medicine in treatment of metabolic syndrome. Endocr Metab Immune Disord Drug Targets 2008;8:99111. [217] Brusq JM, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y, et al. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res 2006;47:12818. [218] Chang X, Yan H, Fei J, Jiang M, Zhu H, Lu D, et al. Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats. J Lipid Res 2010;51:250415. [219] Turner N, Li JY, Gosby A, To SW, Cheng Z, Miyoshi H, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes 2008;57:141418. [220] Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y, et al. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS One 2011;6:e16556. [221] Yuan X, Wang J, Tang X, Li Y, Xia P, Gao X. Berberine ameliorates nonalcoholic fatty liver disease by a global modulation of hepatic mRNA and lncRNA expression profiles. J Transl Med 2015;13:24. [222] Yan HM, Xia MF, Wang Y, Chang XX, Yao XZ, Rao SX, et al. Efficacy of berberine in patients with non-alcoholic fatty liver disease. PLoS One 2015;10:e0134172. [223] Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004;10:134451. [224] Hardie DG. Sensing of energy and nutrients by AMP-activated protein kinase. Am J Clin Nutr 2011;93:891S6S. [225] Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 2006;55:225664.

I. Sirtuins and metabolic disease

References

59

[226] Sun Y, Xia M, Yan H, Han Y, Zhang F, Hu Z, et al. Berberine attenuates hepatic steatosis and enhances energy expenditure in mice by inducing autophagy and fibroblast growth factor 21. Br J Pharmacol 2018;175:37487. [227] Noumi E, Snoussi M, Alreshidi MM, Rekha PD, Saptami K, Caputo L, et al. Chemical and biological evaluation of essential oils from cardamom species. Molecules 2018;23(2818):118. Available from: https://doi.org/10.3390/molecules23112818. [228] Amma KPAP, Rani MP, Sasidharan I, Nisha VNP. Chemical composition, flavonoid-phenolic contents and radical scavenging activity of four major varieties of cardamom. Int J Biol Med Res 2010;1(3):204. [229] Sharma S, Sharma J, Kaur G. Therapeutic uses of Elettaria cardomum. Int J Drug Formulation Res 2011;2:1028. [230] Bhattacharjee B, Chatterjee J. Identification of proapoptopic, anti-inflammatory, anti-proliferative, anti-invasive and anti-angiogenic targets of essential oils in cardamom by dual reverse virtual screening and binding pose analysis. Asian Pac J Cancer Prev 2013;14:373542. [231] Vaidya A, Rathod M. An in vitro study of the immunomodulatory effects of Piper nigrum (black pepper) and Elettaria cardamomum (cardamom) extracts using a murine macrophage cell line. AIJRFANS 2014;8:1827. [232] Daneshi-Maskooni M, Keshavarz SA, Qorbani M, Mansouri S, Alavian SM, Badri-Fariman M, et al. Green cardamom increases Sirtuin-1 and reduces inflammation in overweight or obese patients with non-alcoholic fatty liver disease: a double-blind randomized placebocontrolled clinical trial. Nutr Metab 2018;15:63. [233] Darwish MM, Abd El Azime AS. Role of cardamom (Elettaria cardamomum) in ameliorating radiation induced oxidative stress in rats. Arab J Nucl Sci Appl 2013;46:2329. [234] Bhat GN, Nayak N, Vinodraj K, Chandralekha N, Mathai P, Cherian J. Comparison of the efficacy of cardamom (Elettaria cardamomum) with pioglitazone on dexamethasone-induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats. J Adv Pharm Technol Res 2015;6:136. [235] Sadeek EA, El-Razek FHA. The chemo-protective effect of turmeric, chili, cloves and cardamom on correcting iron overload-induced liver injury, oxidative stress and serum lipid profile in rat models. J Am Sci 2010;6:7. [236] Winarsi H, Yuniaty A, Nuraeni I. Improvement of antioxidant and immune status of atherosclerotic rats adrenaline and egg-yolksinduced using cardamom-rhizome-ethanolic-extract: an initial study of functional food. Agric Agric Sci Proc 2016;9:26470. [237] Rahman MM, Alam MN, Ulla A, Sumi FA, Subhan N, Khan T, et al. Cardamom powder supplementation prevents obesity, improves glucose intolerance, inflammation and oxidative stress in liver of high carbohydrate high fat diet induced obese rats. Lipids Health Dis 2017;16:151. [238] Han X, Parker TL. Cardamom (Elettaria cardamomum) essential oil significantly inhibits vascular cell adhesion molecule 1 and impacts genome-wide gene expression in human dermal fibroblasts. Cogent Med 2017;4:1308066. [239] Suneetha WJ, Krishnakantha T. Cardamom extract as inhibitor of human platelet aggregation. Phytother Res 2005;19:43740. [240] Kazemi S, Yaghooblou F, Siassi F, Rahimi Foroushani A, Ghavipour M, Koohdani F, et al. Cardamom supplementation improves inflammatory and oxidative stress biomarkers in hyperlipidemic, overweight, and obese pre-diabetic women: a randomized doubleblind clinical trial. J Sci Food Agric 2017;97:5296301. [241] Al-Othman AM, Ahmad F, Al-Orf S, Al-Murshed KS, Arif Z. Effect of dietary supplementation of Ellataria cardamomum and Nigella sativa on the toxicity of rancid corn oil in Rats. Int J Pharmacol 2006;2:605. [242] Alvarez-Cilleros D, Ramos S, Goya L, Martin MA. Colonic metabolites from flavanols stimulate nitric oxide production in human endothelial cells and protect against oxidative stress-induced toxicity and endothelial dysfunction. Food Chem Toxicol 2018;115:8897. [243] Mahabir A, Motilal LA, Gopaulchan D, Ramkissoon S, Sankar A, Umaharan P. Development of a core SNP panel for cacao (Theobroma cacao L.) identity analysis. Genome 2019;. [244] Duarte DA, Mariana ABR, Papadimitriou A, Silva KC, Amancio VHO, Lopes de Faria JB, et al. Polyphenol-enriched cocoa protects the diabetic retina from glial reaction through the sirtuin pathway. J Nutr Biochem 2015;26:6474. [245] Chinni SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH. Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 2001;20:2927. [246] Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 2005;4:120115. [247] Chang H-P, Wang M-L, Chan M-H, Chiu Y-S, Chen Y-H. Antiobesity activities of indole-3-carbinol in high-fat-dietinduced obese mice. Nutrition 2011;27:46370. [248] Chang H, Wang M, Hsu C, Liu M, Chan M, Chen Y-H. Suppression of inflammation-associated factors by indole-3-carbinol in mice fed high-fat diets and in isolated, co-cultured macrophages and adipocytes. Int J Obes 2011;35:1530. [249] Choi Y, Kim Y, Park S, Lee KW, Park T. Indole-3-carbinol prevents diet-induced obesity through modulation of multiple genes related to adipogenesis, thermogenesis or inflammation in the visceral adipose tissue of mice. J Nutr Biochem 2012;23:17329. [250] Choi Y, Um SJ, Park T. Indole-3-carbinol directly targets SIRT1 to inhibit adipocyte differentiation. Int J Obes 2013;37:8814. [251] Hsu Y-C, Wu Y-T, Yu T-H, Wei Y-H. Mitochondria in mesenchymal stem cell biology and cell therapy: from cellular differentiation to mitochondrial transfer. Seminars in cell & developmental biology. Elsevier; 2016. p. 11931. [252] Lai CS, Tsai ML, Badmaev V, Jimenez M, Ho CT, Pan MH. Xanthigen suppresses preadipocyte differentiation and adipogenesis through down-regulation of PPARgamma and C/EBPs and modulation of SIRT-1, AMPK, and FoxO pathways. J Agric Food Chem 2012;60:1094101.

I. Sirtuins and metabolic disease

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4 Sirtuins in diabetes mellitus and diabetic kidney disease Kultigin Turkmen Division of Nephrology, Department of Internal Medicine, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey O U T L I N E 4.1 Introduction

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Part 1 4.2 Sirtuin 1 (SIRT1) in normal physiology

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Part 2 4.3 Diabetes mellitus and sirtuins

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4.4. Hypertension and sirtuins 4.5. Novel treatment options in diabetes mellitus and diabetic kidney disease

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4.6. Conclusion and future perspectives

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References

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4.1 Introduction Sirtuins are a group of NAD-dependent enzymes that consist of seven different structural subtypes, SIRT1 to SIRT7 (Table 4.1). Mainly they remove the acetyl groups from lysine residues of various enzymes, transcription factors, and also histones of DNA. There are two possibilities for the effects of deacetylation of the proteins mentioned above. The first possibility is the activation of transcription factors. In this case, the system can be activated or inhibited according to transcription factor activity. The second possibility is the inhibition of the target factors and in this case again the system can be activated or inhibited. However, on the contrary, deactylated histones cause downregulation of their target proteins. Sir 2 was the first sirtuin identified in Saccharomyces cerevisae. After the discovery of Sir 2 in yeast, researchers showed that these enzymes could prolong life. After the discovery of the role of prolonging life, studies were initiated to identify the members of the sirtuin family in mammals and many articles have been published on this subject up to the present. From a search in Pubmed, we can see that the current number of articles on sirtuins is around 12,000 and this number is increasing day by day. In my opinion, the main reason why the Sirtuin family is very popular among researchers is that these enzymes control life-leading mechanisms and pathways. In particular, calorie restriction (CR)-induced effects activate sirtuins and eventually induce organ protection and increase cell survival (Fig. 4.1). Diabetes mellitus (DM) and its complications are worldwide problems. The prevalence of DM is growing, probably due to increased consumption of food and decreased physical activity. According to the American Diabetes Association (ADA) data, in 2017 an estimated 24.7 million people in the United States were diagnosed with DM, representing 7.6% of the total population (and 9.7% of the adult population). The estimated national cost of diabetes in 2017 is US$ 327 billion, of which US$ 237 billion (73%) represents direct health care expenditures attributed to diabetes and US$ 90 billion (27%) represents lost productivity from work-related absenteeism, reduced productivity at work and at home, unemployment from chronic disability, and premature mortality in Sirtuin Biology in Cancer and Metabolic Disease. DOI: https://doi.org/10.1016/B978-0-12-822467-0.00014-0

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© 2021 Elsevier Inc. All rights reserved.

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4. Sirtuins in diabetes mellitus and diabetic kidney disease

TABLE 4.1 The locations and functions of sirtuin family members. Sirtuin group

Enzyme localization

Enzyme activity

SIRT1

Cytoplasm and nucleus

Deacetylase

SIRT2

Cytoplasm and nucleus

Deacetylase

SIRT3

Cytoplasm, mitochondrion and nucleus

Deacetylase

SIRT4

Mitochondrion

ADP-ribosyl transferase

SIRT5

Mitochondrion

Deacetylase

SIRT6

Nucleus

Deacetylase and ADP-ribosyl transferase

SIRT7

Nucleus

Deacetylase

FIGURE 4.1 The relation between calorie restriction, NAD, and sirtuins.

the United States [1]. Hence, we should initiate new strategies and develop new treatment modalities to overcome these problems. In this chapter, first of all, I would like to focus on the physiological functions of sirtuins, and thereafter I will comprehensively discuss the pathophysiological roles of sirtuins in DM and related diseases, including hypertension and diabetic nephropathy.

Part 1 4.2 Sirtuin 1 (SIRT1) in normal physiology In the cell, the localization of sirtuins is very important for their functions. Sirtuin 1 (SIRT1) is found both in the nucleus and cytoplasm. Because of its widespread localization, SIRT1 might have various physiological and maybe pathological metabolic effects under certain stress conditions. The main functions of this molecule include deacetylating nuclear histone proteins as well as deacetylation of nonhistone proteins including peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α), insulin receptor substrate-1 (IRS-2), peroxisome proliferator-activated receptor-alpha (PPAR-α), PPAR-γ, mitochondrial uncoupling protein 2 (UCP-2), liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory-element binding protein (SREBP) [2 6]. By deacetylating histone proteins in the nucleus by SIRT1, repression of gene transcription

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occurs [7]. On the other hand, the metabolic effects of SIRT1 regulate insulin secretion, adipogenesis, and myogenesis. Hence, SIRT1 is the most common member of sirtuins, probably due to the generalized effects on the cell cycle, mitochondria metabolism, energy homeostasis, inflammation, oxidative stress, and apoptosis [8]. However, other sirtuins might play a role regarding the functions of mitochondria. For instance, SIRT5 regulates the urea cycle through the direct activation of carbamoyl phosphate synthetase [9]. Subsequent studies have revealed that SIRT5 also exhibits demalonylase and desuccinylase activities, through which it controls ketogenesis [10]. An important effect of SIRT5 as an inducer of the energetic flux via glycolysis has also been shown [11]. After deactylation of transcription factors or histones the second important step is conversion of nicotinamide adenine dinucleotide (NAD) to nicotinamide (NAM). We understood that without NAD, SIRT1 cannot exert its functions. On the other hand, NAD is reduced to NADH in mitochondria under certain conditions. Therefore NAD should be supplied via salvage and de novo pathways. In the salvage pathway, NAM can be converted to nicotinamide mononucleotide (NMN) by the enzyme “intracellular NAM phosphoribosyl transferase” (iNampt) and thereafter NMN is converted to NAD via the enzyme named “nicotinamide mononucleotide adenyl transferases2” (Nmnat). On the contrary, in the de novo pathway, NAD is obtained from tryptophan and nicotinic acid by various enzymes [12]. In this regard, I would like to continue with the metabolic effects of SIRT1, 3, and 4 in mammals.

4.2.1 Major roles of SIRT1 in glucose metabolism SIRT1 can influence many steps of glucose metabolism in liver, pancreas, muscle, and adipose tissue (Fig. 4.2). Mainly SIRT1 affects cell metabolism by deacetylating and activating PGC-1α [13]. During the fasting state, the balance between insulin and glucagon (decreased insulin versus increased glucagon) stimulates gluconeogenesis. Modulation of gluconeogenesis occurs via cAMP-response element binding protein (CREB), regulated transcription coactivator 2 (CRTC2), and Forkhead box 1 (FOXO1) (Fig. 4.3) [14,15]. The latter is one of the most important transcriptional factors, and has been found to be very effective in terms of sensing nutrient deprivation and promoting cellular homeostasis [16]. The link between FOXO proteins, signal transducer and activator of transcription 3 (STAT3), and SIRT1 regarding hepatic glucose metabolism has also been identified. FOXO1, -3a, and -4 were found to be closely associated with increased expression of gluconeogenesis genes and decreased expression of glucokinase [17,18]. SIRT1 also regulates gluconeogenesis via deacetylation, thereby deactivating STAT3 which can inhibit the transcription of gluconeogenic genes in normal conditions [19]. In this context, FOXO proteins along with STAT3 and SIRT1 regulate glucose metabolism [20] and feeding behaviors [21]. Insulin sensitivity has also been considered to be an important part of the glucose metabolism. Protein tyrosine phosphatase 1B (PTP1B) is a tyrosine phosphatase for the insulin receptor that has been found to have an important role in insulin sensitivity and diet-induced obesity [22]. PTP1B can be repressed via deacetylation. Activation

FIGURE 4.2 Metabolic effects of SIRT1 in peripheral organs.

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FIGURE 4.3 The enzymes involved in glucose and lipid metabolism.

of SIRT1 inhibits PTP1B. In this regard, SIRT1 might improve insulin sensitivity in insulin-resistant conditions via reducing PTPB1B activity [23]. The role of SIRT1 in the pancreas was also demonstrated. Experimental data of SIRT1 overexpression suggested that serum insulin and cholesterol were diminished along with the diminution of the adipose tissue volume and decreased obesity-induced insulin resistance [24,25]. Interestingly, SIRT1-deficient mice also exhibit low levels of serum glucose and insulin [26]. Despite the repetitive results of the studies regarding the CR-induced SIRT1 expression, Moynihan et al. [6] demonstrated that β-cell-specific SIRT1 transgenic mice exhibit insulin secretion ex vivo in pancreatic β-islet cells in response to high glucose. This result was confirmed by Bordone et al. [26] who also pointed out that insulin secretion was reduced in SIRT1 knockout mice and in pancreatic β-islet cell lines in which SIRT1 had been knocked down by RNA interference. UCP-2 is a mitochondrial inner membrane protein that regulates mitochondrial ATP synthesis. The effects mentioned above partially depend on the SIRT1-mediated inhibition of UCP-2 protein in pancreatic islet β-cells [6]. In accordance, SIRT1 knockout mice exhibit increased UCP-2 in β-cells along with low levels of serum insulin [26]. Higher pancreatic secretion of insulin and ATP were demonstrated in UCP-2 knockout mice [27]. According to these study results, SIRT1 might be a positive regulator rather than a suppressor of insulin in the postprandial fed state.

4.2.2 Major roles of SIRT1 in lipid metabolism In the fasting state, free fatty acids (FFA) are one of the main energy sources of our body. PPAR-α increases mitochondrial free fatty acid β oxidation via SIRT1-induced PGC1-α deactylation in the liver and striated and smooth muscles (Figs. 4.2 and 4.3) [3]. In addition, SIRT1 knockout mice exhibit hepatosteatosis due to accumulation of fats in the liver [28]. However, PPAR-γ, which is another important regulator of adipogenesis from the PPAR family, is inactivated by SIRT1. In this regard, inhibition of PPAR-γ causes diminished adipogenesis, therefore obesity, and increases free fatty acid release in white adipose tissue [29]. Liver kinase B1 (LKB1) is a primary upstream kinase of adenosine monophosphate-activated protein kinase (AMPK), a necessary element in cell metabolism that is required for maintaining energy homeostasis. SIRT1 stimulates LKB1 and AMPK that enhance fatty acid β-oxidation in the liver [30]. In contrast, SIRT1 inhibits SREBP 1 and this inhibition results in increased lipolysis in the liver [2]. Liver X receptor-alpha (LXR-α) and beta (LXR-β) are nuclear receptor proteins in humans which are encoded by the NR1H3 and NR1H2 genes (nuclear receptor subfamily 1, group H3 and H2), respectively. Another regulatory function of SIRT1 is cholesterol biosynthesis. LXR-α and LXR-β are two important nuclear proteins that maintain and control synthesis of cholesterol. These proteins stimulate the activation of ABCA-1 that results in high-density lipoprotein (HDL) synthesis. In this context, Li et al. [31] showed that deacetylation of LXR proteins might be associated with the pathogenesis of atherosclerosis, especially in chronic metabolic disorders including diabetes. Farnesoid X receptor (FXR), also known as bile acid receptor, another member of the nuclear receptor family, was found to be closely related to glucose and lipid metabolism. Deacetylation of FXR by SIRT1 represses the activation of this protein, and therefore the deleterious metabolic effects were inhibited [32]. In the following section, I will continue with the roles of sirtuins in terms of the pathogenesis of DM.

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4.2.3 Major roles of SIRT3 in glucose metabolism and lipid metabolism SIRT 3, a mitochondria localized sirtuin, also has beneficial effects on glucose metabolism by increasing insulin sensitivity and decreasing serum glucose. Hirschey et al. recently demonstrated that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. According to the results of this study, increased obesity, insulin resistance, hyperlipidemia, and steatohepatitis are prominent in mice lacking SIRT3 compared to wild-type mice [33]. The same group also identified a single nucleotide polymorphism which encodes a point mutation in the SIRT3 protein. As a result, mitochondrial protein acetylation is impaired and polymorphism of SIRT3 has been shown to be associated with metabolic syndrome [33]. SIRT3 is also involved in the pathogenesis of hepatic lipid metabolism by deacetylating and activating longchain acyl CoA dehydrogenase [34].

4.2.4 Major roles of SIRT4 in glucose and lipid metabolism Another important sirtuin that takes part in glucose metabolism is SIRT4. In contrast to SIRT1, both the localization and the function of SIRT4 are different. SIRT4 is located in mitochondria and transfers ADP-ribose to the substrates. One of the target enzymes of SIRT4 is glutamate dehydrogenase (GDH) which converts glutamate to α-ketoglutarate in the mitochondrion [35]. SIRT4 inhibits amino acid-induced insulin secretion via repression of GDH [36]. During fasting, SIRT4 is found to be inhibited in liver to induce glucogenesis from amino acids and fats and in the meantime inhibition of SIRT4 allows insulin secretion from β-cells. However, SIRT4 is activated and the reactions mentioned above are reversed in fed states [35]. In contrast, SIRT4 has opposite effects on free fatty acid metabolism and induction of SIRT4 might increase hepatosteatosis [37].

Part 2 4.3 Diabetes mellitus and sirtuins DM and its complications have been increasing worldwide during the last decades despite the emergence of diagnostic tools and therapeutic applications. Hence, DM has been accepted as an epidemic worldwide, except in Africa. The prevalence of DM is growing probably due to increased consumption of food and decreased physical activity. According to the ADA data, in 2017 an estimated 24.7 million people were diagnosed with DM in the United States [1]. Besides the increase in prevalence and incidence of DM, morbidity and mortality are also increasing in this population. In this regard, diabetes was both found to be closely associated with cardiovascular morbidity and mortality [38]. Traditional risk factors including hyperglycemia, insulin resistance hyperlipidemia, and so forth can be recognized and treated, however, today we can not achieve the desired results. The most important questions are what are the main struggles faced by clinicians and how can they deal with these problems in diabetic patients? wFirst of all, internists, endocrinologist, nephrologists, and cardiologists encounter difficulties regarding diabetic macro- and microvascular complications even in diabetic patients with strict blood glucose level and blood pressure control [39,40]. Additionally, the entire pathophysiology of this chronic metabolic disorder remains mysterious despite the advances in diagnostic and therapeutic strategies. To date, novel risk factors, including increased inflammatory cytokines due to low-grade persistent inflammation [41], adipose tissue hormones (adipokines), including obstatin, leptin, resistin, and the renin angiotensin aldosterone system are determined as the most detrimental factors attributed to this heightened CV morbidity and mortality in diabetic and obese patients [42 44]. There are some treatment options to overcome novel risk factors [45,46], however, it is illogical to treat these various entities separately. Therefore the main source of the detrimental pathogenetic mechanisms should be determined and new therapeutic molecules should be identified to accomplish the treatment of diabetes. In this context, three main questions should be answered. First, what are the main attributed pathways to overcome these undesirable pathophysiologic events in normal physiology? Second, why do these unwanted

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events occur despite defensive mechanisms? And third, are there any novel treatment modalities to treat diabetes and its complications? To answer these questions we have to highlight additional pathophysiological mechanisms. In the following part of this chapter we aimed to bring out these novel pathways regarding sirtuins.

4.3.1 The roles of sirtuins in the pathogenesis of diabetes mellitus As mentioned above, DM and its complications are worldwide problems that we should overcome. Insulin resistance is the prominent risk factor and as a result hyperinsulinemia occurs in the early stages of type 2 DM. Impaired glucose uptake and utilization follow this stage and hyperglycemia and hyperinsulinemia contribute to the pancreatic β-islet cell destruction in the following stages of diabetes [44,47]. At the end, hyperglycemia and related metabolic alterations, including advanced glycation end products (AGEs), polyol, hexosamine, and protein kinase C pathways, collectively contribute to the classical pathogenesis of DM. The main reasons for the undesirable complications of DM might be due to unknown pathophysiological mechanisms. In this context, as mentioned above, SIRT1 induces gluconeogenesis and inhibits glycolysis in liver during fasting via deacetylating FOXO1 and PGC1α. One of the most important question is how do these changes regarding gluconeogenesis and glycolysis occur? Rodgers et al. [48] demonstrated that hepatic PGC1α is upregulated and gluconeogenesis is increased, which can further increase hyperglycemia in diabetic mice. Yechoor et al. [49] showed that SIRT3 mRNA is downregulated in the muscle insulin receptor knockout mice. Another study demonstrated that SIRT3 induces the ketogenesis by activating acetyl Co-A synthetase in the mammalian cells [50]. Hence, one might expect that SIRT3 might play an important role in the increased ketogenesis observed in DM.

4.3.2 Sirtuins and diabetic kidney disease Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and an independent risk factor for cardiovascular diseases [51]. All cell types of kidney including glomerular podocytes, mesangial, tubular, endothelial, and interstitial cells can be affected by hyperglycemic injury. Glomerular basement membrane thickening, mesangial expansion, and glomerular podocyte loss are the main features involved in DKD [52]. Regardless of the cause, glomerular sclerosis, interstitial fibrosis, and tubular atrophy are the final consequences. In normal physiology, SIRT1 is extensively expressed from proximal and distal tubular cells as well as podocytes [53]. SIRT1 is also found to be involved in water and sodium physiology. In this regard, SIRT1 decreases the transcription of alpha subunits of eNaC channels and therefore decreases sodium and water reabsorption in the distal tubules [54]. Another system which has very active players in the progression of DKD is the renin angiotensin aldosterone system (RAAS). Among them, angiotensin II (ANG II), is the most studied molecule and plays a key role in the development and progression of diabetic nephropathy. Angiotensin 1 7, a metabolic by-product ameliorates the effects of ANG II. Previous studies showed that ANG 1 7 can activate ERK1/2 and cAMP/protein kinase A-dependent pathways in glomerular mesangial and proximal tubular cells (PTCs) [55,56] and was found to be protective in terms of DKD in Zucker diabetic fatty rats [57]. Recently, Mori et al. reported that ANG 1 7 ameliorates DKD and reduces tubulointerstitial fibrosis (TIF) and inflammation in the kidney via the SIRT1-FOXO1 pathway [58]. In addition, decreased expression of SIRT1 is found to be closely associated with increased transcription of angiotensin II type 1 receptor (AT1R) in podocytes [59]. However, increased expression of SIRT1 downregulates AT1R in vascular smooth muscle cells [60]. Collectively, in the pathologic conditions, SIRT1 is found to be protective against various injury to tubules and glomerulus [61 63]. Like SIRT1, SIRT3 also has a role in the kidney [64]. As we know very well, the functions of SIRT3 are closely related to mitochondrial energy homeostasis and antioxidant defense in proximal and distal tubules which have a very high number of mitochondria [65,66] In this regard, Perico et al. [67] demonstrated that SIRT3 can mediate microtubule network-dependent trafficking of functional mitochondria between renal tubular epithelial cells. This process preserves the proper cellular bioenergetic profile and antioxidant defense in PTCs. 4.3.2.1 What are the effects of SIRT6 and SIRT7 in kidney? SIRT6 has an important role in maintaining glomerular selectivity to plasma proteins. We got these data from the studies done by Huang et al. [68]. Their group clearly showed that deletion of SIRT6 in mice resulted in podocyte injury and decreased slit diaphragm proteins foot process effacement and eventually increased proteinuria. They also concluded that Sirt6 deletion can accelerate renal hypertrophy.

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Although there have been not many studies on SIRT7 in the literature, a few studies have shown that SIRT7 also has an effect on renal functions. The studies regarding SIRT7 demonstrated that this subtype has an ability to deacetylate KCC4 transport protein which is expressed at the basolateral membrane of the α-intercalated cells. This channel can transport potassium with chloride and also has an important role in maintaining pH in the collecting ducts especially during metabolic acidosis [69]. Hence it is wise to consider that SIRT7 can control renal acid base and electrolyte balance. Additionally Miyasato and colleagues [70] recently found that Sirt7 knockout mice were resistant to cisplatin-induced acute kidney injury (AKI). Furthermore, they showed that loss of SIRT7 decreases the expression of tumor necrosis factor-α (TNF-α) by regulating the nuclear expression of the transcription factor nuclear factor kappa B. According to the results of this study, SIRT7 might play an important role in cisplatin-induced AKI and suggest the possibility of SIRT7 as a novel therapeutic target for cisplatin-induced nephrotoxicity. What are the protective effects of SIRT1 in different parts of the kidney? In the following part, I would like to answer this question using data from literature [71].

4.3.3 The roles of SIRT1 in the glomerulus in diabetic kidney disease 4.3.3.1 Results from animal models of diabetes mellitus In the literature, there is an accumulation of data regarding the pathogenetic role of decreased expression of SIRT1 in the DKD (Table 4.2). In this context, Koya and colleagues clearly demonstrated that SIRT1 activity is diminished in type 2 diabetic rats, and these changes were ameliorated by CR [72 75]. Recent studies revealed that mice with 80% knockdown of renal SIRT1 expression have normal glomerular function under the basal condition. However, nephron- and tubulotoxic agents easily compromise the glomerular and tubular functions and lead to end-stage renal failure, especially in patients with DKD. Results obtained from the mice model of diabetes have shown the dark side of sirtuin-related pathways in DKD. For instance, data obtained from diabetic mice model of doxorubicin-induced nephropathy revealed that proteinuria, glomerulosclerosis, mitochondrial injury, and impaired autophagy of damaged mitochondria can occur, especially in SIRT1 deficiency [76]. Replacement of SIRT1 in the early phase of doxorubicin-induced nephropathy prevented the progression of glomerular injury and reduced the accumulation of dysmorphic mitochondria in podocytes but TABLE 4.2 The effects of SIRT1 and associated pathways in cell culture and animal models of diabetes mellitus. Tissue/cell type

Animal model/cell culture

Target protein/ enzyme/ pathway

Definition of SIRT1 effect

References

Glomerulus STZ-diabetic mice

Histone H3, Activation of SIRT1 by resveratrol treatment involves change in MAP kinase p38, phosphorylation of histone H3, expression of Sir-2, p53, and p38 in p53 DKD.

[75]

Glomerulus Diabetic WFR

NF-kβ

Increased inflammation through increased NF-kβ secondary to decreased SIRT1.

[73]

Proteinuria, glomerulosclerosis, mitochondrial injury and impaired autophagy of damaged mitochondria can occur especially in SIRT1 deficiency

[76]

Glomerulus Doxurubicin-induced nephropathy in diabetic rat Tubulus

Cell culture

Foxo3a

SIRT1 protects against oxidative stress-induced proximal tubule cell apoptosis by acetylation of FOXO3a

[77]

Tubulus

Cell culture

Foxo3a, Bnip3

SIRT1 can induce Bnip3 associated mitochondrial autophagy through FOXO3 pathway.

[72]

Mesangial cells

Cell culture

AMPK, mTOR

SIRT 1 augments AMPK and inhibits mTOR pathways

[78]

Mesangial cells

Cell culture

Smad7

Inhibition of Smad7 by SIRT1 decreases TGFβ-induced apoptosis

[79]

Mesangial cells

Cell culture

p53

Inhibition of p53 by SIRT1 decreases oxidative stress-induced apoptosis

[80]

Podocytes

Cell culture

Foxo4

Inhibition of Foxo4 by SIRT1 decreases AGE-induced apoptosis

[81]

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did not reverse the progression of glomerulosclerosis and proteinuria. Chuang et al. [76] also demonstrated that SIRT1 knockdown mice with DM developed more albuminuria and mitochondrial dysfunction compared with diabetic mice without SIRT1 knockdown. Recently, Hasegawa et al. [82] showed the close relation between PTC and podocytes. In this regard, they demonstrated that metabolic effects mediated by glucose in PTC affected podocytes and eventually increased albuminuria. In detail, high glucose in PTC decreased SIRT1 levels and thereafter decreased NMN levels. This can cause a vicious cycle because decreased NMN levels further decrease SIRT1 in podocytes. The decrease in SIRT1 in podocytes induces many reactions. Among these reactions, deacetylation of H3 and H4 histones via SIRT1 inducing DNA methylation of the CpG islands around the claudin-1 gene is the most important step. This reaction is activated by DNA methyl transferase (DNMT). After DNA methylation, the claudin-1 gene is activated and increases claudin-1 expression which interacts with the β-catenin/snail pathway. Eventually, activation of the latter pathway induces decreased podocin and snaptopodin protein and at the end of these alterations foot process effacement and proteinuria occurs. The importance of this study is that researchers clearly showed proximal tubule podocyte interaction occurred before well-known mechanisms including tubuloglomerular feedback and glomerular tubular balance. In this context, altogether the results mentioned above clearly show the beneficial effects of SIRT1 in terms of homeostatic maintenance of podocytes under stress conditions. 4.3.3.2 Results from cell culture studies Cell culture is an indispensable method for understanding the exact pathological pathways. In this regard, the exact roles of SIRT1 in the glomerular cells has been clarified by the results of cultured mesangial cells and podocytes (Table 4.2). In cultured mesangial cells, oxidative stress-related apoptosis was suppressed by SIRT1 via deacetylation of p53 [83] and TGF β-related apoptosis was also found to be inhibited by SIRT1 via deacetylation of Smad7 [79]. Recently, Zhua et al. demonstrated that NAD concentration and SIRT 1 activity of the mesangial cell were reduced when these cells were exposed to high glucose [84]. Additionally, advanced glycated end-product was found to be an inducer of apoptosis of podocytes via increasing Foxo4. Activation of SIRT1 deacetylates and inhibits Foxo4, therefore protecting podocytes from AGE-induced apoptotic cell death in diabetes [81]. In this regard, SIRT1 may act as a guardian against apoptotic cell death or hypertrophy of the mesangial cells and podocytes in DKD. Hence, it might be wise to consider the therapeutic approaches activating SIRT1 in the early phase of DKD before the onset of sclerotic lesions.

4.3.4 The roles of SIRT1 in the tubulointerstitium in diabetic kidney disease Oxidative stress is enormously high in the renal medulla, especially due to hypoxia and hypertonicity. In recent studies, SIRT1 was excessively detected in the interstitial cells of the renal medulla, when compared with the renal cortex. It is wise to hypothesize that excessive SIRT1 activity can fight with excessive oxidative stress in this part of the kidney. Some in vitro studies support this theory. In this regard, He et al. [77] showed the beneficial effects of SIRT1 activation in terms of oxidative stress in the interstitium of renal medulla. 4.3.4.1 Results from animal models of diabetes mellitus In this part of the review, we would like to describe the role of SIRT1 in the pathogenesis of diabetic TIF. In the progression of DKD, tubular atrophy and interstitial fibrosis eventually occur. Hence, one of the aims of the therapy of DKD should include the prevention of diabetic TIF. Previous studies demonstrated that SIRT1 can act as an antifibrotic molecule through Smad3 and TGF-β pathways which were mentioned above as common players in the pathogenesis of DKD [77,85]. Another system which has very active players in the progression of DKD is the RAAS. Among them, angiotensin II (ANG II), is the most studied molecule and plays a key role in the development and progression of diabetic nephropathy. Angiotensin 1 7 is a metabolic by-product that ameliorates the effects of ANG II. Previous studies showed that ANG 1 7 can activate ERK1/2 and cAMP/protein kinase A-dependent pathways in glomerular mesangial and PTCs [55,56] and was found to be protective in terms of DKD in Zucker diabetic fatty rats [57]. Recently, Mori et al. [58] reported that ANG 1 7 ameliorates DKD and reduces TIF and inflammation in the kidney via the SIRT1-FOXO1 pathway. In light of these data, we should consider renin angiotensin aldosterone system blockers in the treatment of DKD.

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4.3.4.2 Results from cell culture studies From the results of cell culture studies, we have learned that increased activity of renal tubular SIRT1 might attenuate diabetic albuminuria by epigenetically suppressing claudin-1 overexpression in podocytes [82]. Additionally, direct renoprotective effects of SIRT1 overexpression in proximal tubular epithelial cells were also shown. In this regard, SIRT1 was shown to be a defender against renal tubular cell apoptosis by inducing catalase through the deacetylation of FOXO3 in vivo [62]. Furthermore, Hasegawa et al. [61] also demonstrated that renal proximal tubular cell-specific SIRT1 transgenic mice were resistant against cisplatin-induced apoptosis and tubulopathy by enhancing medium-chain acyl-CoA dehydrogenase, which is a rate-limiting enzyme of mitochondrial β oxidation. In another study, SIRT1 activated PGC-1α and activation of this enzyme is found to induce PTC repair via activating mitochondrial functions [86] and oxidative phosphorylation [87]. Kim and collegues also reported that the activation of SIRT1 by resveratrol diminished cisplatin-induced proximal tubular cell apoptosis through the deacetylation of p53 [80]. In the following section, I would like to mention the novel pathways and sirtuins involved in the pathogenesis of DM and DKD. Among them, I will start with the relation between autophagy and SIRT1. Thereafter, I will continue with AMPK pathway, which is the most important pathway of energy sensation in diabetes. Eventually I will get onto the mTOR pathway and discuss the relationship with sirtuins regarding diabetes and DKD.

4.3.5 The roles of SIRT1 and autophagy in diabetes mellitus and diabetic kidney disease Autophagy is a tightly regulated degradation process that involve many complicated reactions and ultimately ends with lysosomal degradation of nonuseful proteins and organelles [88]. This lysosomal degradation pathway is considered essential for homeostasis, development, differentiation, and survival of the organisms [89]. The role of autophagy in metabolic disorders is currently under intense investigation and it has been revealed that autophagy has a protective role in pancreatic β-cells against various deleterious stresses [90,91]. Physiological situations, such as nutrient starvation, antiaging, cell growth control, tumor suppression, and inherent immunity, and pathological insults, such as hypoxia, energy depletion, and drugs (mTOR inhibitors such as sirolimus), may induce autophagy. Many nutrient-sensing pathways, including AMPK, are involved in autophagy, especially in starvation [92]. Alteration of these pathways under hyperglycemic conditions may impair the autophagic response stimulated by miscellaneous stresses. One of the important studies in the literature showed that autophagy-deficient mice had pancreatic β-cell degeneration and impaired glucose tolerance with reduced insulin secretion. The results of this study clearly suggest that the degradation of unnecessary cellular components by autophagy is essential for maintenance of the architecture and function of pancreatic β-cells [90]. Among other, especially SIRT1 was found to be one of the positive regulators of autophagy. In this regard, the decrease in SIRT1 expression observed in the diabetic kidney may lead to the dysregulation of autophagy. Recent studies clearly showed that in proximal tubule cells SIRT1 decreased albuminuria in DM through maintaining NMN concentrations around glomeruli and controlling podocyte function [82,93]. In addition, SIRT1 was found to be closely associated with the survival of cells in an affected kidney by modulating their responses to various stress stimuli, taking part in arterial blood pressure control, protecting against cellular apoptosis in renal tubules by catalase induction, and triggering autophagy. The phosphorylation of AMPK positively regulated SIRT1 [94] and thereafter autophagy [95], was also decreased in the DKD. Hence, activation of SIRT1 may become a novel target in the treatment of diabetic nephropathy [44,96]. The role of autophagy in diabetes was also shown in mice deficient of an autophagy related protein named sequestosome 1 (Sqstm1/p62). The Sqstm1/p62-deficient mice exhibit severe hyperglycemia and eventually diabetes [97]. Kitada et al. [73] demonstrated accumulation of Sqstm1/p62 in the PTCs of diabetic Wistar Fatty Rats (WFRs) kidneys, which means that an impairment of the autophagy system occurred in DKD. They also showed that restoration of SIRT1 expression and AMPK activation via CR improved the function of the autophagy system, which resulted in normalization of mitochondrial morphological changes and Sqstm1/p62 accumulation in the kidney of WFRs. According to the results of this study, the existence of autophagosomes in the PTCs of the kidney in WFRs treated with CR was consistent with the existence of normal morphological mitochondria. What effects can be seen in podocytes regarding the relation between sirtuins and autophagy? In this context, Hartleben et al. [98] gave careful attention to podocytes as sites of “an unusually high level of constitutive autophagy.” They advocated that autophagic pathways can be activated against podocytopathy to diminish proteinuria in mice. Inhibition of autophagy by lacking one of the autophagosomal genes, Atg5, was found to be closely associated with proteinuria. In this regard, autophagy might play a protective role against podocyte injury.

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4.3.6 The roles of SIRT1 and adenosine monophosphate-activated protein kinase pathway in diabetic kidney disease In normal physiology, AMPK may activate the phosphorylation of acetyl-CoA-carboxylase, which results in decreased lipogenesis and enhanced lipolysis. So, AMPK is activated under energy-depleted conditions and is likely to be suppressed in diabetic nephropathy. Hence, suppression in AMPK activity in DKD may trigger lipogenesis and thereafter lipotoxicity-associated kidney injury may occur in susceptible kidneys. Decreased phosphorylation of AMPK which in turn inactivated AMPK was reported in the glomerulus and tubules in animal models of type 1 and type 2 DM [78,99,100]. In addition, glomerular and tubular lesions are reversed when AMPK activators such as 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) and metformin are administered in streptozosin (STZ)-induced DKD [101]. AMPK activity and plasma adiponectin levels were also found to be significantly lower in db/db diabetic mice when compared with control mice [78]. Additionally, Cammisotto et al. [102] demonstrated that adiponectin might stimulate AMPK activity in podocytes, mesangial cells, and glomerular endothelial cells. Sharma and colleagues also showed decreased podocyte AMPK activity along with albuminuria in mice with DKD [103]. In a study with diabetic akita mice the results clearly demonstrated that activation of AMPK by AICAR significantly improved kidney injury including albuminuria [104]. Many nutrient-sensing pathways including AMPK, mTOR, and sirtuins may also be involved in autophagy especially in starvation [92]. Alteration of these pathways under hyperglycemic conditions may impair the autophagic response stimulated by miscellaneous stresses. Recent research demonstrated that positive effects of resveratrol on glucose metabolism and insulin sensitivity are closely associated with AMPK subunit α activation of this agent rather than the stimulatory effect on SIRT1.

4.3.7 The roles of SIRT1 and mTOR pathway in diabetic kidney disease The third and the last pathway is the mammalian target of rapamycin (mTOR) pathway, which is a serine/ threonine kinase that regulates both cell growth and cell cycle progression through the phosphatidyl 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway. Phosphatidylinositol-3 kinase (PI3K) converts the lipid phosphatidylinositol biphosphate (PIP2) into phosphatidylinositol triphosphate (PIP3), which localizes protein kinase B (Akt) to the membrane. mTOR phosphorylates both ribosomal protein S6 kinases (p70S6K1) and eukaryotic initiation factor 4E-binding proteins (4E-BP1) via independent pathways, resulting in activation of S6K1 and inactivation of 4E-BP1 [105]. Increased p70S6K1 and eIF4E act independently to promote cell growth and cell-cycle progression. Therefore mTOR plays a critical role in transducing proliferative signals mediated through the PI3K/Akt signaling pathway, principally by activating downstream protein kinases that are required for both ribosomal biosynthesis and translation of key mRNAs of proteins required for progression of G1 to S phase [106]. This means that mTOR regulates both cell cycle progression and cell growth. DKD is found to be closely associated with dysregulated cell growth and cell-cycle progression, exaggerated proliferative responses, and increased apoptosis in mesangial and PTCs [107]. In this regard, researchers hypothesized that there might be a link between DKD and the mTOR pathway. Thereafter, many studies showed that there has been a significant early activation of mTOR-dependent pathways that induce podocyte injury, mesangial expansion, glomerular basement membrane thickening, glomerular hypertrophy, and tubular dearrangements in animal models of diabetes [108,109]. One of the attributed mechanisms of the mTOR pathway that leads to interstitial fibrosis is the increased expression of profibrotic cytokines including TGF-β and connective tissue growth factor in DKD [108]. Moreover, administration of rapamycin, an inhibitor of mTOR, to diabetic mice reversed these pathological depositions mentioned above and diminished proteinuria in DKD [110]. Recently, mTOR Complex 1 (mTORC1) activity was found to be essential to maintain podocyte homeostasis, however hyperactivation of mTORC1 may cause glomerular lesions commonly seen in DKD [109,110]. Additionally, podocyte-specific repression of raptor, a component of mTORC1 that inhibits mTOR pathway have demonstrated beneficial effects on mesangial matrix expansion, glomerulosclerosis and eventually proteinuria diabetic mice [111]. In this regard, researchers decided to try rapamycin, an mTOR inhibitor, as a treatment agent to attenuate glomerular and mesangial lesions commonly seen in DKD. Rapamycin was found to be beneficial in terms of mesangial expansion and glomerular basement membrane thickness in rats with DKD [112]. The first reports are promising and in the near future rapamycin might be a therapeutic option in DKD.

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4.4 Hypertension and sirtuins Most diabetic patients have hypertension. The pathogeneses of both diabetes and hypertension have similarities. So we can say that diabetes and hypertension are twins. As mentioned, a close relation has been revealed between sirtuins and diabetes. The main question is whether or not sirtuins are also associated with blood pressure control. In this context, recent studies have attempted to find a link between hypertension (HT) and SIRT1. The plausible explanation regarding the relation between HT and SIRT1 came from the study done by Miyazaki and colleagues. Their group have demonstrated that SIRT1 overexpression reduces the expression of the angiotensin-1 (AT1) receptor of angiotensin II (AT1R) in vivo, while nicotinamide, a SIRT1 inhibitor, increases this expression [60]. Additionally, they reported that the SIRT 1 activator, resveratrol, negatively regulated AT1R expression via reducing specificity protein 1 (Sp1) in cultured vascular smooth muscle cells and suppressed AT1R in the aorta and reversed HT in mice [60]. SIRT1 also promotes vasodilation by deacetylating nitric oxide (NO) synthetase in the endothelial cells [8]. In a recent study, endothelial NO was found to be crucial in SIRT1associated CR-induced cardioprotection and blood pressure control [113]. The role of aldosterone in the pathogenesis of HT has been well-known for years. Renal tubular sodium reabsorption via epithelial sodium channels (eNac) in the apical membranes of collecting duct principal cells is the primary target of aldosterone. Increased levels of serum aldosterone induce eNac expression of collecting tubular cells which contribute HT [114]. In this regard, Zhang et al. [54] demonstrated that SIRT1 can diminish the expression of eNac alpha subunits via hypermethylation of a histone H3K79 methyltransferase (also named disruptor of telomeric silencing 1). This effect was found to be independent of both deacetylase activity of SIRT1 and the mineralocorticoid signaling pathway. In addition to the experimental studies investigating the relation between SIRT1 and HT, a recent clinical study revealed that SIRT1 gene polymorphism (rs2273773) was significantly associated with ambulatory blood pressure levels in Han Chinese patients with hypertension [115]. This experimental and clinical evidence collectively demonstrated that in the near future SIRT1 might be a candidate target molecule in the treatment of HT.

4.5 Novel treatment options in diabetes mellitus and diabetic kidney disease Because much research has demonstrated various positive effects of sirtuins on glucose, lipid, and carbohydrate metabolism, scientists also attempted to translate these data into pharmaceuticals. In this context, resveratol, is a plant polyphenol, was the first molecule introduced as a SIRT1 inducer [116]. Much experimental data showed the beneficial effects of resveratrol in animals. Yamazaki et al. [117] showed that treatment of mice with nonalcoholic fatty liver disease with a synthetic SIRT1 activator, SRT1720, might decrease the serum lipid levels, oxidative stress, and inflammation. In addition, Feig et al. [118] showed that activation of SIRT1 by SRT1720 protected the organism from diet-induced insulin resistance and obesity via increasing oxidation of fat in liver, adipose tissue, and skeletal muscle. Also SRT3025 which is another SIRT1 activator is found to improve glycemic control with greatly reduced islet α-cell mass and lower plasma glucagon concentrations [119]. However, in the following years, it was demonstrated that positive effects of resveratol on glucose metabolism and insulin sensitivity are closely associated with AMPK subunit α activation of this agent rather than the stimulatory effect on SIRT1. In this regard, Um et al. [120], for the first time, demonstrated that resveratrol could not improve glucose tolerance and insulin sensitivity in AMPK α knockout mice. In humans, Timmers et al. [121] also showed the beneficial effects of resveratrol in obese patients in terms of lowering systolic blood pressure, serum lipid and glucose levels, and inflammation parameters. Beside resveratrol and SIRT1 synthetic activators, NMN, a NAD1 intermediate, is another molecule that has been demonstrated to have beneficial effects by improving glucose and lipid levels in aging-induced diabetes [122]. Additionally, niacin, vitamin B3, is also an important intermediate for the biosynthesis of NAD1 that can used for the activation of SIRT1 [123]. Another molecule that has been tried to increase sirtuin activity is curcumin. Curcumin is a polyphenol extracted from the rhizome of Curcuma longa. In a study done by Ortega-Dominguez et al. [124] curcumin was found to prevent the increase of mitochondrial fission 1 protein, and the decrease of NAD-dependent deacetylase SIRT3 in cisplatin-induced AKI. They also showed that the mitophagy associated proteins parkin and phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1) were found to be decreased. According to the results of this study, curcumin might ameliorate the tubular damage and renal complications by preserving redox balance and mitochondrial bioenergetics via SIRT3 activation.

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There is also SIRT3 activators. One of them is honokiol which is an active compound of Magnolia officinalis. M. officinalis is a well-known antiinflammatory and antioxidant herbal medicine which has been widely used in China [125]. In this context, honokial is found to decrease insulin resistance by targeting PTP1B and decrease glucose levels in type 2 diabetic mice [126]. Recently, Li et al. [127] demonstrated that honokiol might be beneficial via SIRT3-induced deacetylation of a transcription factor named KLF15 and thereafter decreases angiotensin-2 induced fibrosis in hypertension-induced chronic kidney disease. In addition, another study also showed that activation of SIRT3 via honokiol treatment might have beneficial effects on unilateral ureteral obstructioninduced renal fibrosis through SIRT3-dependent regulation of mitochondrial functions and the NF-κB/TGF-β1/ Smad signaling pathway [128]. Slybin (also known as silibinin) is a major active constituent of silymarin, a standardized extract of the milk thistle seeds. Wang et al. [129] studied the effects of SIRT1 and autophagy in streptozotocin-induced DM and assessed the protective mechanism of silibinin in terms of relationship between autophagy and SIRT1. They concluded that systemic administration of silibinin reversed streptozotocin-induced downregulation of SIRT1 expression and SIRT1 might play a role in regulating the physiological level of autophagy. Hence, silibinin may reverse hyperglycemia and repair damaged pancreatic β-cells via the promotion of SIRT1 expression and recovering autophagy. Stanniocalcin-1 has antioxidant and antiapoptotic activities, which play a role in kidney protection, including DKD. A recent study suggested that stanniocalcin-1 ameliorates oxidative stress and cell apoptosis in the kidneys of db/db mice and high glucose-treated cells by inhibiting Bnip3 expression through AMPK/Sirt3 pathway activation [130]. Thus the authors concluded that stanniocalcin-1 might become a potential drug for the treatment of DKD patients. 5-Aminoimidazole-4-carboximide riboside (AICAR) is also tested in diabetic mice regarding the energy sensing pathway including AMPK [131]. Data are limited regarding the relation between SIRT and AICAR in DKD, however, in a mice model of AKI, Morigi et al. [132] showed that treatment with the AMPK agonist AICAR or the antioxidant agent acetyl-L-carnitine (ALCAR) restored SIRT3 expression and activity, improved renal function, and decreased tubular injury in wild-type animals, but had no effect in Sirt32/2 mice. Moreover, they demonstrated that Sirt3-deficient mice given cisplatin experienced more severe AKI than wild-type animals and died, and neither AICAR nor ALCAR treatment prevented death in Sirt32/2 AKI mice. However, there are also conflicting results regarding the effects of novel synthetic SIRT1 activators on glucose and lipid metabolism. SIRT1 activators might induce insulin secretion and sensitivity, and reduce adipogenesis, but also induce gluconeogenesis in the liver, that may worsen hyperglycemia in diabetic. Additionally, nowadays neither resveratrol nor the other agents mentioned above are approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA). So how can clinicians use these data regarding sirtuins in their daily practice? In this context, CR provides a desirable metabolic profile and improvement of the mitochondrial functions in humans via activating several genes including SIRT1 [133]. Hence, CR with increased physical activity should be encouraged, especially in obese diabetic patients. The second option in our hand is metformin, which is a commonly used antidiabetic agent. Metformin decreases insulin resistance and hyperglycemia via inhibiting gluconeogenesis and hepatic glucose output and activation of free fatty acid oxidation in skeletal muscle [134]. Some of these beneficial effects of metformin were attributed to SIRT1 activation via the AMPK pathway [135]. Hence, among the mentioned treatment options, except for metformin and CR, none of them as been used in a large series of clinical trials. To date, therefore, it is wise to use only metformin along with CR in obese type 2 diabetic patients to get beneficial metabolic effects. Lastly, in this section, I would like to mention mesenchymal stromal cell (MSC) transplantation which is found to restore kidney impairment and provide renoprotection in a mice model of cisplatin-induced kidney injury. In this context, a recent study revealed that MSCs-transplanted mice with cisplatin-induced AKI showed improved mitochondrial biogenesis in proximal tubules by enhancing PGC1α expression, NAD1 biosynthesis, and SIRT3 activity. However, in MSC-treated SIRT3-deficient mice, these beneficial effects could not be seen. Hence, the authors concluded that MSCs transplantation into mice with AKI might stimulate renal tubular cell growth and enhance mitochondrial function via SIRT3 [67].

4.6 Conclusion and future perspectives Inflammation, oxidative stress, apoptosis, autophagy, and various endogenous pathways are involved in the pathogenesis and progression of DM. Sirtuins are key molecules that might exert renoprotective effects by modulating these pathways. Hence, activation of sirtuins, especially SIRT1 and SIRT3, might result in various beneficial

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metabolic effects, making these proteins a target for new drugs, especially for the future treatment of DM and DKD. However, there are many missing pieces in the puzzle and further experiments and clinical studies are needed to highlight the exact roles of sirtuins in DM.

References [1] Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care 2018;41(5):917 28. [2] Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, et al. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev 2010;24(13):1403 17. [3] Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 2009;9(4):327 38. [4] Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P. Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 2008;582(1):46 53. [5] Zhang J. The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation. J Biol Chem 2007;282 (47):34356 64. [6] Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Meneur C, et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab 2005;2(2):105 17. [7] Vaquero A, Scher M, Erdjument-Bromage H, Tempst P, Serrano L, Reinberg D. SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 2007;450(7168):440 4. [8] Kitada M, Kume S, Takeda-Watanabe A, Kanasaki K, Koya D. Sirtuins and renal diseases: relationship with aging and diabetic nephropathy. Clin Sci (Lond) 2013;124(3):153 64. [9] Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 2009;137(3):560 70. [10] Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 2013;18(6):920 33. [11] Nishida Y, Rardin MJ, Carrico C, He W, Sahu AK, Gut P, et al. SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol Cell 2015;59(2):321 32. [12] Hasegawa K. Novel tubular-glomerular interplay in diabetic kidney disease mediated by sirtuin 1, nicotinamide mononucleotide, and nicotinamide adenine dinucleotide Oshima Award Address 2017. Clin Exp Nephrol 2019;23(8):987 94. [13] Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434(7029):113 18. [14] Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC1alpha interaction. Nature 2003;423(6939):550 5. [15] Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 2005;437(7062):1109 11. [16] Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004;117(4):421 6. [17] Yeagley D, Guo S, Unterman T, Quinn PG. Gene- and activation-specific mechanisms for insulin inhibition of basal and glucocorticoidinduced insulin-like growth factor binding protein-1 and phosphoenolpyruvate carboxykinase transcription. Roles of forkhead and insulin response sequences. J Biol Chem 2001;276(36):33705 10. [18] Ayala JE, Streeper RS, Desgrosellier JS, Durham SK, Suwanichkul A, Svitek CA, et al. Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. Diabetes 1999;48(9):1885 9. [19] Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, et al. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Med 2004;10(2):168 74. [20] Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, et al. A fasting inducible switch modulates gluconeogenesis via activator/ coactivator exchange. Nature 2008;456(7219):269 73. [21] Sasaki T, Kim HJ, Kobayashi M, Kitamura YI, Yokota-Hashimoto H, Shiuchi T, et al. Induction of hypothalamic Sirt1 leads to cessation of feeding via agouti-related peptide. Endocrinology 2010;151(6):2556 66. [22] Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999;283(5407):1544 8. [23] Sun C, Zhang F, Ge X, Yan T, Chen X, Shi X, et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 2007;6(4):307 19. [24] Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 2008;8(4):333 41. [25] Bordone L, Cohen D, Robinson A, Motta MC, van Veen E, Czopik A, et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 2007;6(6):759 67. [26] Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 2006;4(2):e31. [27] Imai S, Johnson FB, Marciniak RA, McVey M, Park PU, Guarente L. Sir2: an NAD-dependent histone deacetylase that connects chromatin silencing, metabolism, and aging. Cold Spring Harb Symp Quant Biol 2000;65:297 302. [28] Wang RH, Li C, Deng CX. Liver steatosis and increased ChREBP expression in mice carrying a liver specific SIRT1 null mutation under a normal feeding condition. Int J Biol Sci 2010;6(7):682 90. [29] Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004;429(6993):771 6.

I. Sirtuins and metabolic disease

74

4. Sirtuins in diabetes mellitus and diabetic kidney disease

[30] Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 2008;283(29):20015 26. [31] Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell 2007;28(1):91 106. [32] Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, et al. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 2009;10(5):392 404. [33] Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 2011;44(2):177 90. [34] Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010;464(7285):121 5. [35] Bordone L, Guarente L. Sirtuins and beta-cell function. Diabetes Obes Metab 2007;9(Suppl. 2):23 7. [36] Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ, Castronovo V, et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem 2007;282(46):33583 92. [37] Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 2010;285(42):31995 2002. [38] Skyler JS, Oddo C. Diabetes trends in the USA. Diabetes Metab Res Rev 2002;18(Suppl. 3):S21 6. [39] Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577 89. [40] Gerstein HC, Riddle MC, Kendall DM, Cohen RM, Goland R, Feinglos MN, et al. Glycemia treatment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007;99(12A):34i 43i. [41] Demirtas L, Turkmen K, Kandemir FM, Ozkaraca M, Kucukler S, Gurbuzel M, et al. The possible role of interleukin-33 as a new player in the pathogenesis of contrast-induced nephropathy in diabetic rats. Ren Fail 2016;38(6):952 60. [42] Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol 2014;63(4):250 9. [43] Baloglu I, Turkmen K, Selcuk NY, Tonbul HZ, Ozcicek A, Hamur H, et al. The relationship between visceral adiposity index and epicardial adipose tissue in patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2019;. [44] Turkmen K. Inflammation, oxidative stress, apoptosis, and autophagy in diabetes mellitus and diabetic kidney disease: the Four Horsemen of the Apocalypse. Int Urol Nephrol 2017;49(5):837 44. [45] Onk D, Onk OA, Turkmen K, Erol HS, Ayazoglu TA, Keles ON, et al. Melatonin attenuates contrast-induced nephropathy in diabetic rats: the role of interleukin-33 and oxidative stress. Mediators Inflamm 2016;2016:9050828. [46] Buyuklu M, Kandemir FM, Ozkaraca M, Set T, Bakirci EM, Topal E, et al. Benefical effects of lycopene against contrast medium-induced oxidative stress, inflammation, autophagy, and apoptosis in rat kidney. Hum Exp Toxicol 2015;34(5):487 96. [47] Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 2006;212(2):167 78. [48] Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A 2007;104(31):12861 6. [49] Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, et al. Distinct pathways of insulin-regulated versus diabetesregulated gene expression: an in vivo analysis in MIRKO mice. Proc Natl Acad Sci U S A 2004;101(47):16525 30. [50] Hallows WC, Lee S, Denu JM. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A 2006;103 (27):10230 5. [51] Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 2011;7(6):327 40. [52] Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest 2004;34(12):785 96. [53] Morigi M, Perico L, Benigni A. Sirtuins in renal health and disease. J Am Soc Nephrol 2018;29(7):1799 809. [54] Zhang D, Li S, Cruz P, Kone BC. Sirtuin 1 functionally and physically interacts with disruptor of telomeric silencing-1 to regulate alphaENaC transcription in collecting duct. J Biol Chem 2009;284(31):20917 26. [55] Liu GC, Oudit GY, Fang F, Zhou J, Scholey JW. Angiotensin-(1-7)-induced activation of ERK1/2 is cAMP/protein kinase A-dependent in glomerular mesangial cells. Am J Physiol Ren Physiol 2012;302(6):F784 90. [56] Gava E, Samad-Zadeh A, Zimpelmann J, Bahramifarid N, Kitten GT, Santos RA, et al. Angiotensin-(1-7) activates a tyrosine phosphatase and inhibits glucose-induced signalling in proximal tubular cells. Nephrol Dial Transpl 2009;24(6):1766 73. [57] Giani JF, Burghi V, Veiras LC, Tomat A, Munoz MC, Cao G, et al. Angiotensin-(1-7) attenuates diabetic nephropathy in Zucker diabetic fatty rats. Am J Physiol Ren Physiol 2012;302(12):F1606 15. [58] Mori J, Patel VB, Ramprasath T, Alrob OA, DesAulniers J, Scholey JW, et al. Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity. Am J Physiol Ren Physiol 2014;306(8):F812 21. [59] Chandel N, Ayasolla K, Wen H, Lan X, Haque S, Saleem MA, et al. Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes. Exp Mol Pathol 2017;102(1):97 105. [60] Miyazaki R, Ichiki T, Hashimoto T, Inanaga K, Imayama I, Sadoshima J, et al. SIRT1, a longevity gene, downregulates angiotensin II type 1 receptor expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2008;28(7):1263 9. [61] Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, et al. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem 2010;285(17):13045 56. [62] Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, et al. Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression. Biochem Biophys Res Commun 2008;372(1):51 6. [63] Turkmen K. Comment on “Renal Protective Effect of Sirtuin 1”. J Diabetes Res 2015;2015:780903. [64] Turkmen K, Karagoz A, Kucuk A. Sirtuins as novel players in the pathogenesis of diabetes mellitus. World J Diabetes 2014;5(6):894 900.

I. Sirtuins and metabolic disease

References

75

[65] Benigni A, Perico L, Macconi D. Mitochondrial dynamics is linked to longevity and protects from end-organ injury: the emerging role of sirtuin 3. Antioxid Redox Signal 2016;25(4):185 99. [66] Perico L, Morigi M, Benigni A. Mitochondrial sirtuin 3 and renal diseases. Nephron 2016;134(1):14 19. [67] Perico L, Morigi M, Rota C, Breno M, Mele C, Noris M, et al. Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function. Nat Commun 2017;8(1):983. [68] Huang W, Liu H, Zhu S, Woodson M, Liu R, Tilton RG, et al. Sirt6 deficiency results in progression of glomerular injury in the kidney. Aging (Albany NY) 2017;9(3):1069 83. [69] Adriana Mercado ZM, Tovar A, Rajaram R, Cruz-Rangel S, Ryu D, Torres N, et al. The K 1 :Cl-cotransporter KCC4 is activated by deacetylation induced by the sirtuin7 (SIRT7). FASEB 2015;29(1). [70] Miyasato Y, Yoshizawa T, Sato Y, Nakagawa T, Miyasato Y, Kakizoe Y, et al. Sirtuin 7 deficiency ameliorates cisplatin-induced acute kidney injury through regulation of the inflammatory response. Sci Rep 2018;8(1):5927. [71] Guclu A, Erdur FM, Turkmen K. The emerging role of sirtuin 1 in cellular metabolism, diabetes mellitus, diabetic kidney disease and hypertension. Exp Clin Endocrinol Diabetes 2016;124(3):131 9. [72] Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K, Araki S, et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest 2010;120(4):1043 55. [73] Kitada M, Takeda A, Nagai T, Ito H, Kanasaki K, Koya D. Dietary restriction ameliorates diabetic nephropathy through antiinflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes. Exp Diabetes Res 2011;2011:908185. [74] Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305(5682):390 2. [75] Tikoo K, Singh K, Kabra D, Sharma V, Gaikwad A. Change in histone H3 phosphorylation, MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy. Free Radic Res 2008;42:397 404. [76] Chuang PY, Xu J, Dai Y, Jia F, Mallipattu SK, Yacoub R, et al. In vivo RNA interference models of inducible and reversible Sirt1 knockdown in kidney cells. Am J Pathol 2014;184(7):1940 56. [77] He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, et al. Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Invest 2010;120(4):1056 68. [78] Kitada M, Kume S, Imaizumi N, Koya D. Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes 2011;60(2):634 43. [79] Kume S, Haneda M, Kanasaki K, Sugimoto T, Araki S, Isshiki K, et al. SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation. J Biol Chem 2007;282(1):151 8. [80] Kim DH, Jung YJ, Lee JE, Lee AS, Kang KP, Lee S, et al. SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. Am J Physiol Ren Physiol 2011;301(2):F427 35. [81] Chuang PY, Dai Y, Liu R, He H, Kretzler M, Jim B, et al. Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PLoS One 2011;6(8):e23566. [82] Hasegawa K, Wakino S, Simic P, Sakamaki Y, Minakuchi H, Fujimura K, et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med 2013;19(11):1496 504. [83] Kume S, Haneda M, Kanasaki K, Sugimoto T, Araki S, Isono M, et al. Silent information regulator 2 (SIRT1) attenuates oxidative stressinduced mesangial cell apoptosis via p53 deacetylation. Free Radic Biol Med 2006;40(12):2175 82. [84] Zhuo L, Fu B, Bai X, Zhang B, Wu L, Cui J, et al. NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuinsAMPK-mTOR pathway. Cell Physiol Biochem 2011;27(6):681 90. [85] Li J, Qu X, Ricardo SD, Bertram JF, Nikolic-Paterson DJ. Resveratrol inhibits renal fibrosis in the obstructed kidney: potential role in deacetylation of Smad3. Am J Pathol 2010;177(3):1065 71. [86] Tran MT, Zsengeller ZK, Berg AH, Khankin EV, Bhasin MK, Kim W, et al. PGC1alpha drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 2016;531(7595):528 32. [87] Funk JA, Schnellmann RG. Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1alpha activation following ischemia-reperfusion injury. Toxicol Appl Pharmacol 2013;273(2):345 54. [88] Turkmen K, Martin J, Akcay A, Nguyen Q, Ravichandran K, Faubel S, et al. Apoptosis and autophagy in cold preservation ischemia. Transplantation 2011;91(11):1192 7. [89] Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008;132(1):27 42. [90] Fujitani Y, Kawamori R, Watada H. The role of autophagy in pancreatic beta-cell and diabetes. Autophagy 2009;5(2):280 2. [91] Demirtas L, Guclu A, Erdur FM, Akbas EM, Ozcicek A, Onk D, et al. Apoptosis, autophagy & endoplasmic reticulum stress in diabetes mellitus. Indian J Med Res 2016;144(4):515 24. [92] Tanaka Y, Kume S, Kitada M, Kanasaki K, Uzu T, Maegawa H, et al. Autophagy as a therapeutic target in diabetic nephropathy. Exp Diabetes Res 2012;2012:628978. [93] Bible E. Diabetic nephropathy: Sirt1 attenuates diabetic albuminuria. Nat Rev Nephrol 2013;9(12):696. [94] Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab 2010;298(4):E751 60. [95] Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010;40(2):280 93. [96] Polak-Jonkisz D, Laszki-Szczachor K, Rehan L, Pilecki W, Filipowski H, Sobieszczanska M. Nephroprotective action of sirtuin 1 (SIRT1). J Physiol Biochem 2013;69(4):957 61. [97] Geetha T, Zheng C, Vishwaprakash N, Broderick TL, Babu JR. Sequestosome 1/p62, a scaffolding protein, is a newly identified partner of IRS-1 protein. J Biol Chem 2012;287(35):29672 8. [98] Hartleben B, Godel M, Meyer-Schwesinger C, Liu S, Ulrich T, Kobler S, et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest 2010;120(4):1084 96.

I. Sirtuins and metabolic disease

76

4. Sirtuins in diabetes mellitus and diabetic kidney disease

[99] Ding DF, You N, Wu XM, Xu JR, Hu AP, Ye XL, et al. Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am J Nephrol 2010;31(4):363 74. [100] Cammisotto PG, Londono I, Gingras D, Bendayan M. Control of glycogen synthase through ADIPOR1-AMPK pathway in renal distal tubules of normal and diabetic rats. Am J Physiol Ren Physiol 2008;294(4):F881 9. [101] Lee MJ, Feliers D, Mariappan MM, Sataranatarajan K, Mahimainathan L, Musi N, et al. A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. Am J Physiol Ren Physiol 2007;292(2):F617 27. [102] Cammisotto PG, Bendayan M. Adiponectin stimulates phosphorylation of AMP-activated protein kinase alpha in renal glomeruli. J Mol Histol 2008;39(6):579 84. [103] Sharma K, Ramachandrarao S, Qiu G, Usui HK, Zhu Y, Dunn SR, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 2008;118(5):1645 56. [104] Dugan LL, You YH, Ali SS, Diamond-Stanic M, Miyamoto S, DeCleves AE, et al. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J Clin Invest 2013;123(11):4888 99. [105] Turkmen K. The protective effect of mammalian target of rapamycin (mTOR) in cisplatin induced nephropathy. J Med Hypotheses Ideas 2009;3(1):26 33. [106] Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ. p70S6 kinase signals cell survival as well as growth, inactivating the proapoptotic molecule BAD. Proc Natl Acad Sci U S A 2001;98(17):9666 70. [107] Kume S, Thomas MC, Koya D. Nutrient sensing, autophagy, and diabetic nephropathy. Diabetes 2012;61(1):23 9. [108] Lloberas N, Cruzado JM, Franquesa M, Herrero-Fresneda I, Torras J, Alperovich G, et al. Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. J Am Soc Nephrol 2006;17(5):1395 404. [109] Mori H, Inoki K, Masutani K, Wakabayashi Y, Komai K, Nakagawa R, et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun 2009;384(4):471 5. [110] Godel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest 2011;121(6):2197 209. [111] Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest 2011;121(6):2181 96. [112] Yang Y, Wang J, Qin L, Shou Z, Zhao J, Wang H, et al. Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am J Nephrol 2007;27(5):495 502. [113] Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, et al. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2015;308(8): H894 903. [114] Rossier BC, Pradervand S, Schild L, Hummler E. Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu Rev Physiol 2002;64:877 97. [115] Zhong XL, Miao HJ, Fang ZM, Kuken B, Song HY, Zhong H, et al. The effect of SIRT1 gene polymorphisms on ambulatory blood pressure of hypertensive patients in the Kazakh population. Genet Test Mol Biomarkers 2015;19(10):561 5. [116] Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425(6954):191 6. [117] Yamazaki Y, Usui I, Kanatani Y, Matsuya Y, Tsuneyama K, Fujisaka S, et al. Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice. Am J Physiol Endocrinol Metab 2009;297(5):E1179 86. [118] Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab 2008;8(5):347 58. [119] Zhang Y, Thai K, Jin T, Woo M, Gilbert RE. SIRT1 activation attenuates alpha cell hyperplasia, hyperglucagonaemia and hyperglycaemia in STZ-diabetic mice. Sci Rep 2018;8(1):13972. [120] Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010;59(3):554 63. [121] Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011;14(5):612 22. [122] Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(1) intermediate, treats the pathophysiology of dietand age-induced diabetes in mice. Cell Metab 2011;14(4):528 36. [123] Sauve AA. NAD 1 and vitamin B3: from metabolism to therapies. J Pharmacol Exp Ther 2008;324(3):883 93. [124] Ortega-Dominguez B, Aparicio-Trejo OE, Garcia-Arroyo FE, Leon-Contreras JC, Tapia E, Molina-Jijon E, et al. Curcumin prevents cisplatin-induced renal alterations in mitochondrial bioenergetics and dynamic. Food Chem Toxicol 2017;107(Pt A):373 85. [125] Chuang DY, Chan MH, Zong Y, Sheng W, He Y, Jiang JH, et al. Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells. J Neuroinflammation 2013;10:15. [126] Sun J, Fu X, Liu Y, Wang Y, Huo B, Guo Y, et al. Hypoglycemic effect and mechanism of honokiol on type 2 diabetic mice. Drug Des Devel Ther 2015;9:6327 42. [127] Li N, Zhang J, Yan X, Zhang C, Liu H, Shan X, et al. SIRT3-KLF15 signaling ameliorates kidney injury induced by hypertension. Oncotarget 2017;8(24):39592 604. [128] Quan Y, Park W, Jin J, Kim W, Park SK, Kang KP. Sirtuin 3 activation by honokiol decreases unilateral ureteral obstruction-induced renal inflammation and fibrosis via regulation of mitochondrial dynamics and the renal NF-kappaBTGF-beta1/SMAD signaling pathway. Int J Mol Sci 2020;21(2):402 20. [129] Wang Q, Liu M, Liu WW, Hao WB, Tashiro S, Onodera S, et al. In vivo recovery effect of silibinin treatment on streptozotocin-induced diabetic mice is associated with the modulations of Sirt-1 expression and autophagy in pancreatic beta-cell. J Asian Nat Prod Res 2012;14(5):413 23. [130] Liu Z, Liu H, Xiao L, Liu G, Sun L, He L. STC-1 ameliorates renal injury in diabetic nephropathy by inhibiting the expression of BNIP3 through the AMPK/SIRT3 pathway. Lab Invest 2019;99(5):684 97.

I. Sirtuins and metabolic disease

References

77

[131] Madhavi YV, Gaikwad N, Yerra VG, Kalvala AK, Nanduri S, Kumar A. Targeting AMPK in diabetes and diabetic complications: energy homeostasis, autophagy and mitochondrial health. Curr Med Chem 2019;26(27):5207 29. [132] Morigi M, Perico L, Rota C, Longaretti L, Conti S, Rottoli D, et al. Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J Clin Invest 2015;125(2):715 26. [133] Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007;4(3):e76. [134] Caton PW, Nayuni NK, Kieswich J, Khan NQ, Yaqoob MM, Corder R. Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. J Endocrinol 2010;205(1):97 106. [135] Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, et al. Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/ AMPK/ROS pathway and therapeutic effects of metformin. Diabetes 2012;61(1):217 28.

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5 Sirtuins and mitochondrial dysfunction Jian-Li He1,2, Tian-Shi Wang1,2 and Yi-Ping Wang3,4 1

Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China 2State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China 3Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, P. R. China 4Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China O U T L I N E 5.1 Sirtuins are nutrient sensors

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5.4.4 Neurodegeneration 5.4.5 Aging 5.4.6 Tumorigenesis

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5.5 Feasible clinical targets: posttranslational modifications of sirtuins regulate mitochondrial function 85

5.4 Sirtuins and mitochondrial dysfunction in human diseases 82 5.4.1 Diabetes and obesity 83 5.4.2 Cardiovascular diseases 84 5.4.3 Renal disease 84

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5.1 Sirtuins are nutrient sensors Sirtuins are nicotinamide adenine dinucleotide (NAD1)-dependent deacylases. They are evolutionarily conserved from yeast to mammals. The importance of sirtuins is largely based on their ability to sense and respond to nutrients, and to maintain metabolic homeostasis [1]. Sirtuins were initially discovered in the budding yeast (Saccharomyces cerevisiae) contributing to the replicative life span [2]. The mammalian genome encodes seven different paralogues of sirtuins. Mammalian sirtuins show diverse spatial distribution in cells. SIRT1, SIRT6, and SIRT7 localize primarily in the nucleus, while SIRT2 functions in the cytoplasm. SIRT3, SIRT4, and SIRT5 reside within mitochondria [3]. Mitochondria are metabolic organelles serving as cellular powerhouses. Sirtuins have been shown to regulate mitochondrial function with their diverse deacylase activities. Among mitochondrial sirtuins, SIRT3 is the major deacetylase with a broad range of substrates. SIRT3 modulates oxidative phosphorylation, fatty acid oxidation (FAO), reactive oxygen species (ROS) response, and even genomic stability [4 7]. SIRT4 is one of the least wellcharacterized members of the sirtuin family, with deacetylase, lipoamidase, and ADP-ribosylase activities, and which controls multiple metabolic processes, including glutamate and leucine metabolism, FAO, pyruvate oxidation, and mitochondrial dynamics [8 11]. SIRT5 regulates metabolic enzymes involved in the tricarboxylic acid cycle, FAO, and adenosine triphosphate (ATP) synthesis by modulating the acylation status of lysine residues,

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FIGURE 5.1 Sirtuins are nutrient sensors.

such as glutarylation, succinylation, and malonylation [12 14]. How cells modulate the specificity of sirtuins toward different acylation modifications remains poorly understood. The activity of sirtuins is tightly controlled by nutrients, linking the nutrient supply with the acylation status of sirtuins’ substrate. Therefore, sirtuins serve as nutrients sensors within cells. Similarly, many nutrientresponsive signaling proteins, such as insulin-like growth factor 1 (IGF1), the target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK), sense nutrients and regulate cellular metabolic activity correspondingly [15]. These nutrient-sensing pathways often collaborate to sense specific nutrient signals and modulate cellular metabolism and maintain mitochondrial homeostasis [16,17] (Fig. 5.1). Sirtuins balance anabolism and catabolism in response to the sufficiency and scarcity of nutrients such as glucose, lipids, and glutamine. The dysfunction of sirtuins is linked to a deficient response to metabolic stress. Podocyte injury, a contributor to diabetic nephropathy, is at least in part caused by high glucose-induced mitochondria dysfunction. Interestingly, SIRT6 and AMPK were reported to transduce the stress signal of high glucose. SIRT6 was downregulated by high glucose and potentially contributed to podocyte apoptosis [18]. Sirtuins are also involved in the pathogenesis of obesity. Nutrient-rich diet decreased SIRT1 activity to induce SIRT3 hyperacetylation in a model of diet-induced obesity [19]. On the contrary, calorie restriction upregulated the expression of most sirtuins to reprogram mitochondrial metabolism [6,20]. Unlike other sirtuins, SIRT4 was induced in a fed state and is involved in mammalian target of rapamycin complex 1 (mTORC1) activation to trigger anabolic signaling [21]. In addition, sirtuins modulate hepatic cellular metabolism in response to different lipid species. Low-level palmitate treatment showed a beneficial effect by enhancing SIRT3 activity and consequent upregulation of mitochondrial metabolism [22]. Lipid droplet-derived monounsaturated fatty acids were sensed by SIRT1, which further promoted peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α)/peroxisome proliferator-activated receptor α (PPARα)-dependent mitochondrial biogenesis and oxidative metabolism [23]. Interestingly, SIRT7-deficient mice were resistant to high-fat diet-induced fatty liver, obesity, and glucose intolerance [24]. Amino acids are also regulators of sirtuin activity. Glutamine is a major source of carbon and nitrogen for proliferating cells. Amino acid sensor mTORC1 downregulated the activity of SIRT4 to enhance glutamine metabolism during transformation and cancer development [25].

5.2 Sirtuins and mitochondrial biogenesis Mitochondria are responsible for not only energy production, but also biomass production. Mitochondria are believed to have an endosymbiotic origin and have maintained a genome outside the nucleus during evolution. Mitochondria mass is regulated on at least three different levels: (1) biomass production: new mitochondria are built by biomolecules encoded by both nuclear and mitochondrial genome (nDNA and mtDNA) [26]; (2) mitochondria quality control: cellular stress, such as ROS and depolarization agents [27,28], causes damage to mitochondria, necessitating a process termed mitophagy to remove defective mitochondria [29]; and (3) mitochondria dynamics: mitochondria form dynamic tubular networks by fission and fusion in response to cellular metabolic requirements [30]. Sirtuins are involved in regulating the transcription of genes encoding mitochondrial proteins. Sirtuins bind to various transcription regulators of mitobiogenesis to modulate target gene expression. For example, SIRT1 mRNA expression was increased by calorie restriction [31], which further activated PGC-1α to enhance mitochondrial biogenesis [32,33]. SIRT1 also bound to transcription factor v-rel avian reticuloendotheliosis viral oncogene homolog B (RELB) and enhanced mitobiogenesis in immune cells to maintain energy production in monocytes [34]. Interestingly, SIRT1 and PGC-1α were suggested to regulate mitobiogenesis through directly

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localizing into mitochondria. SIRT1 and PGC-1α formed a complex with the mitochondrial transcription factor A (TFAM) [35], which potentially regulated mtDNA replication and transcription (Fig. 5.2A). Activating transcription factor 2 (ATF2) is an important regulator of mitochondrial function. SIRT6-activated PGC-1α gene expression by recruiting phosphorylated ATF2 to PGC1-α and increasing General control non-derepressible 5 (GCN5)dependent PGC-1α acetylation [36,37] (Fig. 5.2A). Another nuclear sirtuin, SIRT7, physically interacted with nuclear respiratory factor 1 (NRF1) and inhibited the transcription of genes encoding mitochondrial ribosomal proteins, resulting in the reversal of stem cell aging [38]. SIRT7 was also shown to regulate the expression of nuclear-encoded mitochondrial proteins by deacetylating transcription factor GA binding protein β1 (GABPβ1) [39] (Fig. 5.2A). In hepatic cells, SIRT7 was reported to be modified by protein arginine methylation, linking glucose availability to the transcription of nuclear-encoded mitoribosomal genes [40]. Sirtuins are regulators of protein translation in mitochondria. The proteins encoded by mtDNA are synthesized by mitochondrial ribosomes. Mitoribosomal proteins are encoded in the nuclear genome, synthesized in the cytoplasm, and transported into mitochondria. Together with mitochondrial rRNAs and tRNAs, which are transcribed from mtDNA, mitoribosomal proteins assemble into functional ribosomes to synthesize mtDNA-encoded proteins [41]. SIRT3 was shown to interact with and deacetylate mitochondrial ribosomal protein L10 (MRPL10). In mouse models and cultured cell lines, MRPL10 hyperacetylation enhanced the translational efficiency of mitoribosomes [42]. Other than the mitoribosome, mitochondrial tRNA is potentially regulated by SIRT3 as well. tRNA methylation is an indispensable process for tRNA maturation and proper function in protein translation. Notably, the methylation step is dependent on a key metabolite, 5,10-methylenetetrahydrofolate, which is generated by a mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) [43]. SIRT3 was shown to deacetylate SHMT2 and increase its catalytic activity [44]. Therefore SIRT3 may control protein synthesis by regulating tRNA methylation and maturation (Fig. 5.2B). Sirtuins are involved in the clearance of damaged mitochondria. Mitophagy is critical for cells to degrade deficient or unnecessary mitochondria. BCL2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) is a key determinant for mitophagy. SIRT1 deacetylated forkhead box O3 (Foxo3) to enhance the expression of Bnip3. Importantly, Bnip3 deacetylation was necessary for preventing kidney damage caused by aging or hypoxia [45] (Fig. 5.2C). It is noteworthy that mitochondrial dynamics is also under the control of sirtuins. Mitochondria undergo elongation and division in response to metabolic signals. Mitofusin 1 (MFN1) and optic atrophy 1 (OPA1), two proteins responsible for mitochondria fusion, turned out to be the substrate for SIRT1 and SIRT3, respectively

FIGURE 5.2 Sirtuins regulate mitochondria biogenesis. (A) Sirtuins control the transcription of mitochondria genes through interacting with transcription factors. (B). SIRT3 regulates mitochondrial protein translation by modulating the MRPL10 acetylation and tRNA methylation. (C) SIRT3 deacetylates FOXO3 to enhance BNIP3 expression and consequent mitophagy. (D) Sirtuins are involved in the regulation of mitochondria dynamics by modulating the activity of MFN1, OPA1, and DRP1.

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(Fig. 5.2D). On one hand, SIRT1 expression was increased in hypoxic cells, leading to deacetylation and stabilization of MFN1. The consequent mitochondria elongation was vital for cells to adapt to low oxygen conditions [46]. On the other hand, SIRT3 deacetylated OPA1 and increased its GTPase activity to protect the mitochondrial network from genotoxic agents in cardiomyocytes [47]. Mitochondria fission counteracts with mitochondria fusion to modulate mitochondrial structure. One of the key drivers of mitochondrial fission is dynamin-related protein 1 (Drp1). SIRT4 suppressed Drp1 phosphorylation, a key step in mitochondrial recruitment of Drp1 (Fig. 5.2D). The interaction between SIRT4 and Drp1 was linked to the invasion and migration of cancer cells [11].

5.3 Sirtuins and mitochondrial metabolism The majority of mitochondrial metabolic enzymes are modified by acylation, and therefore substrates for sirtuins. Recent studies have connected mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) with various metabolic pathways. Mitochondrial sirtuins control the acetylation of key enzymes in specific pathways and regulate FAO, tricarboxylic acid cycle (TCA cycle), urea cycle, and other metabolic pathways. For example, SIRT3 controlled the acetylation and activity of coenzyme A synthetase 2 (ACS2), long-chain acyl-coenzyme A dehydrogenase (LCAD), isocitrate dehydrogenase 2 (IDH2), glutamate dehydrogenase (GDH), and superoxide dismutase 2 (SOD2) [5,6,48 50]. SIRT4 seems to be a versatile regulator of mitochondrial metabolism. SIRT4 used NAD1 to ADP-ribosylate and downregulate GDH activity [51]. In addition, SIRT4 functions as a lipoamidase to regulate pyruvate oxidation. Pyruvate is an important substrate for mitochondria. Dihydrolipoyllysine acetyltransferase (DLAT) is an essential subunit of mitochondrial pyruvate dehydrogenase complex (PDH). Interestingly, glutamine enhanced the lipoamidase activity of SIRT4 to inhibit the lipoyl levels of DLAT, thereby suppressing pyruvate oxidation [8]. SIRT5 has been shown to remove multiple types of acylation modifications. SIRT5 was able to deacetylate, desuccinylate, and deglutarylate carbamoyl phosphate synthetase 1 (CPS1). The deacylase activity of SIRT5 toward CPS1 is essential to upregulate the urea cycle for ammonia detoxification [52 54]. Notably, recent protein succinylome analysis revealed that 29% of mitochondrial proteins were lysine-succinylated. Protein succinylation of mitochondrial proteins also plays a regulatory role in cellular metabolism, such that SIRT5 desuccinylated HMGCS2 to promote ketogenesis in mouse liver [14,55].

5.4 Sirtuins and mitochondrial dysfunction in human diseases Mitochondria are hubs in the metabolic network. Therefore mitochondrial dysfunction disorders cell metabolism and contributes to the development of various human diseases. Because sirtuins are key regulators of mitochondrial function, deregulation of sirtuins leads to aberrant acetylation, or more broadly, acylation of their substrates. Recent investigations have demonstrated that deregulation of sirtuins and mitochondrial function is implicated in multiple human diseases, such as diabetes, heart disease, kidney disease, neurodegeneration, and cancer (Figs. 5.3 and 5.4).

FIGURE 5.3 Sirtuins regulate mitochondrial metabolism and homeostasis by modulating various metabolic enzymes.

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FIGURE 5.4 Schematic overview of the deregulation of sirtuins links to mitochondrial dysfunction and human diseases.

5.4.1 Diabetes and obesity Aberrant mitochondrial function is a significant character of diabetes and obesity. Sirtuins are intensively involved in metabolic disorders of mitochondria. Adiponectin, an antidiabetic adipokine, and its receptor AdipoR1 were shown to be induced by extracellular Ca21 influx to activate CaMKKβ-AMPK-SIRT1-PGC-1α axis, resulting in an increase of mitochondrial mass in myocytes. Therefore disruption of SIRT1 caused mitochondrial dysfunction and insulin resistance in obese animals [56]. SIRT2 is potentially protective for obesity and diabetes. SIRT2 attenuated oxidative stress and mitochondrial dysfunction by increasing the expression of mitochondrial fusion protein Mfn2 and by decreasing the expression of mitochondria-fission protein Drp1 in HepG2 cells. SIRT2 mRNA levels were inversely correlated with indexes of obesity and insulin resistance in peripheral blood mononuclear cells (PBMCs) of human subjects [57]. SIRT3 is a key modulator of mitochondrial function in skeletal muscle and adipose tissue. SIRT3 expression was found to be decreased in the skeletal muscle of type 1 and type 2 diabetic models, while Sirt3-deletion mice exhibited reduced mitochondrial oxidation and impaired insulin signaling in skeletal muscle [58]. Of note, SIRT3 activity and mitochondrial antioxidant defense were decreased in skeletal muscle during human pregnancy and gestational diabetes mellitus [59]. Recent reports demonstrated that genetic ablation of Sirt3 and carnitine acetyltransferase, which disrupted acetyl-lysine turnover in the mitochondria of muscle, promoted insulin resistance and redox stress [60]. SIRT3 activation was also necessary to reduce oxidative stress and prevent mitochondrial dysfunction after intracerebral hemorrhage in diabetic rats [61]. Calcium overload is an important factor causing mitochondrial malfunction. SIRT3 was able to inhibit mitochondrial calcium overload and prevent the loss of brown adipose tissue during obesity and metabolic disorders [62]. SIRT4 regulates mitochondrial metabolism in pancreatic β cells and hepatic cells. SIRT4 was able to ADP-ribosylate GDH and inhibit glutamate oxidation in pancreatic β cells [51]. SIRT4 knockdown increased mitochondrial and FAO gene expression in liver and muscle cells, which might provide therapeutic benefits for type 2 diabetes [9]. SIRT5 plays an important role in regulating the metabolic activities of hepatic cells and pancreatic β cells. Overexpression of hepatic SIRT5 by CRISPR/ Cas9 gene-editing ameliorated the metabolic abnormalities in an obesity mouse model [63] SIRT5 overexpression not only improved the secretory capacity of β cells but also reduced glucolipotoxicity-induced apoptosis when cells were stressed with excess palmitate and glucose [40]. SIRT6 and SIRT7 are irreplaceable in maintaining metabolic homeostasis. The deletion of Sirt6 resulted in severe hypoglycemia, liver steatosis, and promoted obesity and diabetes in mice [64,65]. Activation of hepatic SIRT6 suppressed hepatic gluconeogenesis by increasing GCN5-dependent PGC-1α acetylation [37]. SIRT7 was evidenced to deacetylate NRF1 and modulate the expression of nuclear-encoded mitochondrial genes. Sirt7 deficiency induced multisystemic mitochondrial dysfunction and metabolic disorders in mice [39].

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5.4.2 Cardiovascular diseases Aberrant expression of sirtuins tends to deregulate mitochondrial metabolism, mitochondrial biogenesis, and mitophagy in the cardiovascular system. Cardiac deletion of Sirt1 caused cardiomyopathy, while the activation of SIRT1 by resveratrol reversed the cardiac injuries through PGC-1α-dependent mitochondrial biogenesis [10]. SIRT2 promoted AMPK activation and cardiac metabolism to ameliorate angiotensin II-induced cardiac hypertrophy [66]. Besides, SIRT3 was able to decrease the susceptibility of cardiac-derived cells and adult heart to ischemia reperfusion (IR) injury [67]. Sirt3-knockout mice showed high cardiac lipotoxicity and cardiac dysfunction [68]. SIRT3 worked together with FOXO3A and Parkin to promote mitophagy in cardiomyocytes. However, suppression of SIRT3-FOXO3A-Parkin signaling exacerbated the development of diabetic cardiomyopathy [69]. In addition, SIRT3 was reported to deacetylate SOD2 and promote mitochondrial ROS scavenging. By decreasing ROS level, SIRT3 reduced the vascular inflammation induced by the activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome [70,71]. In cardiomyocytes, SIRT4 was decreased after myocardial ischemia reperfusion injury, while overexpression of SIRT4 restored mitochondrial function and ameliorated myocardial injury [72]. Sirt5 ablation was accompanied by a strong increase of protein succinylation in mouse heart. This observation suggests that the desuccinylase activity of SIRT5 plays a significant role in cardiac function. In support of this notion, cardiac deletion of Sirt5 decreased FAO, glucose oxidation, and mitochondrial NAD1/NADH in a model of heart muscle hypertrophy [73]. More importantly, loss of Sirt5 led to hypertrophic cardiomyopathy and increased cardiac ischemia reperfusion injury [74,75].

5.4.3 Renal disease In both human patients and mouse models of severe diabetic kidney disease, expression of SIRT1 was decreased in kidney glomeruli, proximal tubules, and podocytes [76,77]. On the contrary, upregulation of SIRT1 by calorie restriction enhanced Bnip3-dependent mitochondrial autophagy and attenuated hypoxia-associated mitochondrial damage, which is protective in the aged kidney [45]. Similarly, activation of the SIRT1/PGC-1α pathway by SIRT1 activator SRT1720 induced mitochondrial biogenesis and accelerated the recovery of renal function after kidney ischemia reperfusion [78]. These observations indicate that activating SIRT1 is a beneficial therapeutic strategy for kidney disease. Renal SIRT3 level was reported to be associated with oxidative stress and mitochondrial damage. Specifically, cisplatin reduced SIRT3 expression in cultured human tubular cells and caused mitochondrial fragmentation [79]. SIRT3 is potentially linked to renal inflammation. TFAM, a substrate for SIRT3, was shown to mediate the intracellular release of mtDNA and increase renal inflammation and fibrosis [80].

5.4.4 Neurodegeneration Neurodegenerative diseases are tightly connected with mitochondrial dysfunction. Extensive evidence from human patients and mouse models of Huntington’s disease (HD) revealed abnormal mitochondrial permeability transition, defective mitochondrial calcium dynamics, and decreased mitochondrial respiration in HD cerebral cortex and basal ganglia [81 83]. In transgenic and chemical-induced mouse models of HD, SIRT1 activation is critical to protect against motor impairment through multiple targets including the TORC1 and cyclic AMPresponsive element-binding protein (CREB) transcriptional pathway [84,85]. Overactivation of SIRT2 potentially contributed to Alzheimer’s disease (AD) by downregulating the acetylation of tubulin, as SIRT2 inhibition improved microtubule assembly, autophagic vesicle traffic, and mitochondria degradation [86]. Additionally, the neuronal function is affected by mitochondrial sirtuins. SIRT3 deacetylated SOD2 and cyclophilin D in neuronal mitochondria to prevent neuronal death in mouse models of epilepsy and HD [87]. Neuronal SIRT3 was shown to be activated by physiological stress to counteract the degeneration [87]. Sirt4 deletion reduced the expression of glutamate transporter in mouse brain, which was linked to seizure phenotypes [88]. SIRT5 was reported to maintain the expression of SOD2 and mitochondrial antioxidant capacity, explaining its role in ameliorating nigrostriatal dopaminergic degeneration in a mouse model of Parkinson’s disease (PD) [89].

5.4.5 Aging Mutations, deletions, and release of mtDNA contribute to aging [90,91]. Transcriptional factor TFAM is responsible for mtDNA replication and transcription, which are essential for mitochondrial homeostasis. SIRT3

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was shown to deacetylate TFAM and maintain mtDNA integrity [7,92]. Calorie restriction prevents aging with its mechanism not fully understood. Upon calorie restriction, Sirt3 activated Idh2 to increase mitochondrial NADPH level, providing reducing power to support ROS clearance and prevent the age-related hearing loss [49]. Furthermore, SIRT4 was reported to control leucine catabolism and regulate leucine-induced insulin secretion, preventing age-related insulin resistance [10].

5.4.6 Tumorigenesis Mounting evidence suggests that sirtuins play a complex role in tumorigenesis with both tumor-promoting and tumor-suppressing functions. Here we provide an overview of current knowledge of sirtuins in mitochondrial dysfunction and tumorigenesis. SIRT2’s effect on tumor development is probably dependent on the tissue of origin. In human breast cancers and hepatocellular carcinoma, SIRT2 was suggested to be a tumor suppressor through its role in regulating mitosis and genome integrity [90]. However, inactivation of p73 by SIRT2 was critical for the proliferation and tumorigenicity of glioblastoma cells [93]. Moreover, SIRT2 inhibition by a selective inhibitor promoted c-Myc ubiquitination and degradation. SIRT2 inhibitor displayed a broad anticancer effect in various cancer cells [94]. In line with this finding, genetic depletion and pharmacological inactivation of SIRT2 antagonizes aggressive traits and tumorigenesis in basal-like breast cancer [95]. A series of studies have identified SIRT3 as a mitochondria-localized tumor suppressor [96,97]. In human breast tumors, SIRT3 loss resulted in mitochondrial metabolism remodeling and genomic instability [97]. SIRT3 could also destabilize HIF-1α to reduce ROS production and reprogram mitochondrial metabolism in breast cancer cells [98]. In addition, mice with Sirt3 deficiency showed higher expression of iron and transferrin receptor (TfR1) in the pancreas, which contributed to the tumor-suppressive activity of SIRT3 in pancreatic cancers [99]. Interestingly, some studies described SIRT3 as a tumor promoter. SIRT3 knockdown significantly inhibited tumorigenesis in a xenograft model of human melanoma [100]. The expression of SIRT4 is decreased in several types of human tumors, and its lower expression in mitochondria resulted in stress-induced genomic instability and glutamine-dependent proliferation [101]. Due to the intimidate relationship between sirtuins and aging, sirtuins are believed to be promising targets in cancer treatment. A more comprehensive understanding of sirtuins in the malignant transformation and progression of different cancers would aid in target selection and drug screening.

5.5 Feasible clinical targets: posttranslational modifications of sirtuins regulate mitochondrial function The close link between sirtuins and mitochondrial function paves a way to control mitochondria activity by modulating the activity of sirtuin proteins. Similar to their substrates, sirtuins are modified at posttranslational levels as well. The posttranslational modifications (PTM) of sirtuins provide an opportunity for therapeutic intervention of sirtuins. Specifically, the effect of mammalian sirtuins on mitochondrial metabolism has been reported to be regulated by various PTM. For example, phosphorylation of SIRT1, SIRT3, and SIRT6 was demonstrated to control their deacylase activity. SIRT1 is modified by serine phosphorylation. The cAMP/PKA pathway was responsible for SIRT1 phosphorylation, which increased the intrinsic deacetylase activity of SIRT1 to promote PGC-1α deacetylation and FAO [102] (Fig. 5.5A). It is noteworthy that SIRT3, as a vital regulator of mitochondrial stress response in cancer cells, is also modified by phosphorylation. Radiotherapy induced cyclin B1-CDK1 to activate SIRT3 via threonine/serine phosphorylation [103]. In addition, PKCζ phosphorylated SIRT6 to promote its chromatin enrichment and the expression of fatty acid β-oxidation-related genes [104]. Sirtuins are also modified by acetylation, methylation, and SUMOylation. Downregulation of SIRT1 induced SIRT3 hyperacetylation and consequent mitochondrial dysfunction in aging- and obesity-related diseases [19] (Fig. 5.5B). Protein arginine methylation has emerged to modulate the deacetylase activity of sirtuins. SIRT7 was methylated by arginine methyltransferase 6 (PRMT6), which inhibited its histone H3K18 deacetylase activity to promote mitochondrial biogenesis and respiration (Fig. 5.5C) [40]. Protein SUMOylation, referring to the conjugation of small ubiquitinlike protein (SUMO) onto lysine residues of target protein, also modulates mitochondrial activity. During fasting, SUMO-specific protease SENP1 accumulated in the mitochondrial matrix to deSUMOylate and activate SIRT3. This process was indispensable for SIRT3 to promote FAO and maintain energy homeostasis. Importantly, the suppression of SIRT3 deSUMOylation has been demonstrated to prevent HFD-induced obesity [105, 106] (Fig. 5.5D).

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FIGURE 5.5 PTM of sirtuins regulate mitochondrial function. (A) Phosphorylation of SIRT1, SIRT3, and SIRT6 promotes mitochondrial biogenesis and metabolism. (B) SIRT1 downregulation causes SIRT3 hyperacetylation and mitochondrial dysfunction. (C) Methylation of SIRT7 by PRMT6 inhibits its H3K18 deacetylase activity and promotes mitochondrial biogenesis. (D) DeSUMOylation of SIRT3 by SENP1 upregulates its deacetylase activity and mitochondrial metabolism.

Based on their important role in regulating mitochondrial function and cellular metabolism, sirtuins hold great promise to be therapeutic targets in the treatment of human diseases as mentioned above. Further insights into the catalytic and regulatory mechanism of sirtuins will expedite the development of promising inhibitors.

Acknowledgments This work was supported by the Natural Science Foundation of China (Nos. 81790251 and 81772946 to Y.-P.W.), the Young Elite Scientist Sponsorship Program by CAST (2018QNRC001 to Y.-P.W.), High-Level Local University Construction Project of Shanghai Jiao Tong University School of Medicine (18zxy004 to T.-S.W.), Shanghai Committee of Science and Technology (15ZR1424500 to T.-S.W.), and the China Postdoctoral Science Foundation (2019M661548 to J.-L. H.).

References [1] Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403(6771):795 800. [2] Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000;289(5487):2126 8. [3] Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 2005;16(10):4623 35. [4] Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A 2008;105(38):14447 52. [5] Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010;464(7285):121 5. [6] Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010;12(6):662 7. [7] Bagul PK, Katare PB, Bugga P, Dinda AK, Banerjee SK. SIRT-3 modulation by resveratrol improves mitochondrial oxidative phosphorylation in diabetic heart through deacetylation of TFAM. Cells 2018;7(12). [8] Mathias RA, Greco TM, Oberstein A, Budayeva HG, Chakrabarti R, Rowland EA, et al. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 2014;159(7):1615 25. [9] Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 2010;285(42):31995 2002. [10] Anderson KA, Huynh FK, Fisher-Wellman K, Stuart JD, Peterson BS, Douros JD, et al. SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab 2017;25(4):838 55 e15. [11] Fu L, Dong Q, He J, Wang X, Xing J, Wang E, et al. SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway. Oncogene 2017;36(19):2724 36.

I. Sirtuins and metabolic disease

References

87

[12] Wang G, Meyer JG, Cai W, Softic S, Li ME, Verdin E, et al. Regulation of UCP1 and mitochondrial metabolism in brown adipose tissue by reversible succinylation. Mol Cell 2019;74(4):844 57 e7. [13] Nishida Y, Rardin MJ, Carrico C, He W, Sahu AK, Gut P, et al. SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol Cell 2015;59(2):321 32. [14] Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 2013;50(6):919 30. [15] Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD(1) and sirtuin-activating compounds. Nat Rev Mol Cell Biol 2016;17(11):679 90. [16] Silvestre MF, Viollet B, Caton PW, Leclerc J, Sakakibara I, Foretz M, et al. The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions. Life Sci 2014;100(1):55 60. [17] Giovannini L, Bianchi S. Role of nutraceutical SIRT1 modulators in AMPK and mTOR pathway: evidence of a synergistic effect. Nutrition 2017;34:82 96. [18] Fan Y, Yang Q, Yang Y, Gao Z, Ma Y, Zhang L, et al. Sirt6 suppresses high glucose-induced mitochondrial dysfunction and apoptosis in podocytes through AMPK activation. Int J Biol Sci 2019;15(3):701 13. [19] Kwon S, Seok S, Yau P, Li X, Kemper B, Kemper JK. Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3. J Biol Chem 2017;292(42):17312 23. [20] Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey DJ, Selen ES, Boersma MD, et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell 2013;49(1):186 99. [21] Shaw E, Talwadekar M, Rashida Z, Mohan N, Acharya A, Khatri S, et al. Anabolic SIRT4 exerts retrograde control over TORC1 signaling by glutamine sparing in the mitochondria. Mol Cell Biol 2020;40(2):e00212 19. [22] Liu L, Xie B, Fan M, Candas-Green D, Jiang JX, Wei R, et al. Low-level saturated fatty acid palmitate benefits liver cells by boosting mitochondrial metabolism via CDK1-SIRT3-CPT2 cascade. Dev Cell 2020;52(2):196 209 e9. [23] Najt CP, Khan SA, Heden TD, Witthuhn BA, Perez M, Heier JL, et al. Lipid droplet-derived monounsaturated fatty acids traffic via PLIN5 to allosterically activate SIRT1. Mol Cell 2020;77(4):810 24 e8. [24] Yoshizawa T, Karim MF, Sato Y, Senokuchi T, Miyata K, Fukuda T, et al. SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. Cell Metab 2014;19(4):712 21. [25] Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2013;153(4):840 54. [26] Catic A, Suh CY, Hill CT, Daheron L, Henkel T, Orford KW, et al. Genome-wide map of nuclear protein degradation shows NCoR1 turnover as a key to mitochondrial gene regulation. Cell 2013;155(6):1380 95. [27] Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, et al. Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress. EMBO J 2014;33(12):1304 20. [28] Xu SN, Wang TS, Li X, Wang YP. SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation. Sci Rep 2016;6:32734. [29] Zhang Y, Yao Y, Qiu X, Wang G, Hu Z, Chen S, et al. Listeria hijacks host mitophagy through a novel mitophagy receptor to evade killing. Nat Immun 2019;20(4):433 46. [30] Lee H, Yoon Y. Mitochondrial fission and fusion. Biochem Soc Trans 2016;44(6):1725 35. [31] Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007;4(3):e76. [32] Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 2007;26(7):1913 23. [33] Yoon H, Shin SH, Shin DH, Chun YS, Park JW. Differential roles of Sirt1 in HIF-1alpha and HIF-2alpha mediated hypoxic responses. Biochem Biophys Res Commun 2014;444(1):36 43. [34] Liu TF, Vachharajani V, Millet P, Bharadwaj MS, Molina AJ, McCall CE. Sequential actions of SIRT1-RELB-SIRT3 coordinate nuclearmitochondrial communication during immunometabolic adaptation to acute inflammation and sepsis. J Biol Chem 2015;290(1):396 408. [35] Aquilano K, Vigilanza P, Baldelli S, Pagliei B, Rotilio G, Ciriolo MR. Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC1alpha) and sirtuin 1 (SIRT1) reside in mitochondria: possible direct function in mitochondrial biogenesis. J Biol Chem 2010;285(28):21590 9. [36] Yao L, Cui X, Chen Q, Yang X, Fang F, Zhang J, et al. Cold-inducible SIRT6 regulates thermogenesis of brown and beige fat. Cell Rep 2017;20(3):641 54. [37] Dominy Jr. JE, Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol Cell 2012;48(6):900 13. [38] Mohrin M, Shin J, Liu Y, Brown K, Luo H, Xi Y, et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 2015;347(6228):1374 7. [39] Ryu D, Jo YS, Lo Sasso G, Stein S, Zhang H, Perino A, et al. A SIRT7-dependent acetylation switch of GABPbeta1 controls mitochondrial function. Cell Metab 2014;20(5):856 69. [40] Yan WW, Liang YL, Zhang QX, Wang D, Lei MZ, Qu J, et al. Arginine methylation of SIRT7 couples glucose sensing with mitochondria biogenesis. EMBO Rep 2018;19(12):e46377. [41] Couvillion MT, Churchman LS. Mitochondrial ribosome (mitoribosome) profiling for monitoring mitochondrial translation in vivo. Curr Protoc Mol Biol 2017;119 4.28.1 4.28.25. [42] Yang Y, Cimen H, Han MJ, Shi T, Deng JH, Koc H, et al. NAD 1 -dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10. J Biol Chem 2010;285(10):7417 29. [43] Morscher RJ, Ducker GS, Li SH, Mayer JA, Gitai Z, Sperl W, et al. Mitochondrial translation requires folate-dependent tRNA methylation. Nature 2018;554(7690):128 32. [44] Wei Z, Song J, Wang G, Cui X, Zheng J, Tang Y, et al. Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis. Nat Commun 2018;9(1):4468.

I. Sirtuins and metabolic disease

88

5. Sirtuins and mitochondrial dysfunction

[45] Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K, Araki S, et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest 2010;120(4):1043 55. [46] Oanh NTK, Park YY, Cho H. Mitochondria elongation is mediated through SIRT1-mediated MFN1 stabilization. Cell Signal 2017;38:67 75. [47] Samant SA, Zhang HJ, Hong Z, Pillai VB, Sundaresan NR, Wolfgeher D, et al. SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 2014;34(5):807 19. [48] Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A 2006;103(27):10224 9. [49] Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010;143(5):802 12. [50] Pacella-Ince L, Zander-Fox DL, Lane M. Mitochondrial SIRT3 and its target glutamate dehydrogenase are altered in follicular cells of women with reduced ovarian reserve or advanced maternal age. Hum Reprod 2014;29(7):1490 9. [51] Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006;126(5):941 54. [52] Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 2009;137(3):560 70. [53] Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 2014;19(4):605 17. [54] Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 2011;334(6057):806 9. [55] Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 2013;18(6):920 33. [56] Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, et al. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2 1 ) and AMPK/SIRT1. Nature 2010;464(7293):1313 19. [57] Lemos V, de Oliveira RM, Naia L, Szego E, Ramos E, Pinho S, et al. The NAD 1 -dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes. Hum Mol Genet 2017;26(21):4105 17. [58] Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard D, et al. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci U S A 2011;108 (35):14608 13. [59] Boyle KE, Newsom SA, Janssen RC, Lappas M, Friedman JE. Skeletal muscle MnSOD, mitochondrial complex II, and SIRT3 enzyme activities are decreased in maternal obesity during human pregnancy and gestational diabetes mellitus. J Clin Endocrinol Metab 2013;98 (10):E1601 9. [60] Williams AS, Koves TR, Davidson MT, Crown SB, Fisher-Wellman KH, Torres MJ, et al. Disruption of acetyl-lysine turnover in muscle mitochondria promotes insulin resistance and redox stress without overt respiratory dysfunction. Cell Metab 2020;31(1):131 47. [61] Zheng J, Shi L, Liang F, Xu W, Li T, Gao L, et al. Sirt3 ameliorates oxidative stress and mitochondrial dysfunction after intracerebral hemorrhage in diabetic rats. Front Neurosci 2018;12:414. [62] Gao P, Jiang Y, Wu H, Sun F, Li Y, He H, et al. Inhibition of mitochondrial calcium overload by SIRT3 prevents obesity or age-related whitening of brown adipose tissue. Diabetes 2020;69(2):165 80. [63] Du Y, Hu H, Qu S, Wang J, Hua C, Zhang J, et al. SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice. EBioMedicine 2018;36:347 57. [64] Kuang J, Chen L, Tang Q, Zhang J, Li Y, He J. The role of Sirt6 in obesity and diabetes. Front Physiol 2018;9:135. [65] Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010;140(2):280 93. [66] Tang X, Chen XF, Wang NY, Wang XM, Liang ST, Zheng W, et al. SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation 2017;136(21):2051 67. [67] Parodi-Rullan RM, Chapa-Dubocq X, Rullan PJ, Jang S, Javadov S. High sensitivity of SIRT3 deficient hearts to ischemia-reperfusion is associated with mitochondrial abnormalities. Front Pharmacol 2017;8:275. [68] Zeng H, Vaka VR, He X, Booz GW, Chen JX. High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss. J Cell Mol Med 2015;19(8):1847 56. [69] Yu W, Gao B, Li N, Wang J, Qiu C, Zhang G, et al. Sirt3 deficiency exacerbates diabetic cardiac dysfunction: role of Foxo3A-Parkinmediated mitophagy. Biochim Biophys Acta Molecular Basis Disease 2017;1863(8):1973 83. [70] Traba J, Geiger SS, Kwarteng-Siaw M, Han K, Ra OH, Siegel RM, et al. Prolonged fasting suppresses mitochondrial NLRP3 inflammasome assembly and activation via SIRT3-mediated activation of superoxide dismutase 2. J Biol Chem 2017;292(29):12153 64. [71] Chen ML, Zhu XH, Ran L, Lang HD, Yi L, Mi MT. Trimethylamine-N-oxide induces vascular inflammation by activating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. J Am Heart Assoc 2017;6(9):e006347. [72] Zeng G, Liu H, Wang H. Amelioration of myocardial ischemia-reperfusion injury by SIRT4 involves mitochondrial protection and reduced apoptosis. Biochem Biophys Res Commun 2018;502(1):15 21. [73] Hershberger KA, Abraham DM, Martin AS, Mao L, Liu J, Gu H, et al. Sirtuin 5 is required for mouse survival in response to cardiac pressure overload. J Biol Chem 2017;292(48):19767 81. [74] Sadhukhan S, Liu X, Ryu D, Nelson OD, Stupinski JA, Li Z, et al. Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc Natl Acad Sci U S A 2016;113(16):4320 5. [75] Boylston JA, Sun J, Chen Y, Gucek M, Sack MN, Murphy E. Characterization of the cardiac succinylome and its role in ischemiareperfusion injury. J Mol Cell Cardiol 2015;88:73 81. [76] Hasegawa K, Wakino S, Simic P, Sakamaki Y, Minakuchi H, Fujimura K, et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med 2013;19(11):1496 504.

I. Sirtuins and metabolic disease

References

89

[77] Chuang PY, Dai Y, Liu R, He H, Kretzler M, Jim B, et al. Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PLoS One 2011;6(8):e23566. [78] Funk JA, Schnellmann RG. Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1alpha activation following ischemia-reperfusion injury. Toxicol Appl Pharmacol 2013;273(2):345 54. [79] Morigi M, Perico L, Rota C, Longaretti L, Conti S, Rottoli D, et al. Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J Clin Invest 2015;125(2):715 26. [80] Chung KW, Dhillon P, Huang S, Sheng X, Shrestha R, Qiu C, et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis. Cell Metab 2019;30(4):784 99 e5. [81] Choo YS, Johnson GVW, MacDonald M, Detloff PJ, Lesort M. Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet 2004;13(14):1407 20. [82] Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 2002;5(8):731 6. [83] Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, et al. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci: Off J Soc Neurosci 2008;28(11):2783 92. [84] Jeong H, Cohen DE, Cui L, Supinski A, Savas JN, Mazzulli JR, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 2011;18(1):159 65. [85] Jiang M, Wang J, Fu J, Du L, Jeong H, West T, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 2011;18(1):153 8. [86] Silva DF, Esteves AR, Oliveira CR, Cardoso SM. Mitochondrial metabolism power SIRT2-dependent deficient traffic causing Alzheimer’s-disease related pathology. Mol Neurobiol 2017;54(6):4021 40. [87] Cheng A, Yang Y, Zhou Y, Maharana C, Lu D, Peng W, et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab 2016;23(1):128 42. [88] Shih J, Liu L, Mason A, Higashimori H, Donmez G. Loss of SIRT4 decreases GLT-1-dependent glutamate uptake and increases sensitivity to kainic acid. J Neurochem 2014;131(5):573 81. [89] Liu L, Peritore C, Ginsberg J, Shih J, Arun S, Donmez G. Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson’s disease. Behav Brain Res 2015;281:215 21. [90] Kim H-S, Vassilopoulos A, Wang R-H, Lahusen T, Xiao Z, Xu X, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 2011;20(4):487 99. [91] Aarreberg LD, Esser-Nobis K, Driscoll C, Shuvarikov A, Roby JA, Gale Jr. M. Interleukin-1beta induces mtDNA release to activate innate immune signaling via cGAS-STING. Mol Cell 2019;74(4):801 15 e6. [92] Liu H, Li S, Liu X, Chen Y, Deng H. SIRT3 overexpression inhibits growth of kidney tumor cells and enhances mitochondrial biogenesis. J Proteome Res 2018;17(9):3143 52. [93] Funato K, Hayashi T, Echizen K, Negishi L, Shimizu N, Koyama-Nasu R, et al. SIRT2-mediated inactivation of p73 is required for glioblastoma tumorigenicity. EMBO Rep 2018;19(11):e45587. [94] Jing H, Hu J, He B, Negron Abril YL, Stupinski J, Weiser K, et al. A SIRT2-selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anticancer activity. Cancer Cell 2016;29(5):767 8. [95] Zhou W, Ni TK, Wronski A, Glass B, Skibinski A, Beck A, et al. The SIRT2 deacetylase stabilizes slug to control malignancy of basallike breast cancer. Cell Rep 2016;17(5):1302 17. [96] Haigis MC, Deng CX, Finley LW, Kim HS, Gius D. SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res 2012;72(10):2468 72. [97] Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010;17(1):41 52. [98] Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell 2011;19(3):416 28. [99] Jeong SM, Lee J, Finley LW, Schmidt PJ, Fleming MD, Haigis MC. SIRT3 regulates cellular iron metabolism and cancer growth by repressing iron regulatory protein 1. Oncogene 2015;34(16):2115 24. [100] George J, Nihal M, Singh CK, Zhong W, Liu X, Ahmad N. Pro-proliferative function of mitochondrial sirtuin deacetylase SIRT3 in human melanoma. J Invest Dermatol 2016;136(4):809 18. [101] Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013;23(4):450 63. [102] Gerhart-Hines Z, Dominy Jr. JE, Blattler SM, Jedrychowski MP, Banks AS, Lim JH, et al. The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(1). Mol Cell 2011;44(6):851 63. [103] Liu R, Fan M, Candas D, Qin L, Zhang X, Eldridge A, et al. CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor radioresistance. Mol Cancer Ther 2015;14(9):2090 102. [104] Gao T, Li M, Mu G, Hou T, Zhu W-G, Yang Y. PKCζ phosphorylates SIRT6 to mediate fatty acid β-oxidation in colon cancer cells. Neoplasia 2019;21(1):61 73. [105] Wang T, Cao Y, Zheng Q, Tu J, Zhou W, He J, et al. SENP1-Sirt3 signaling controls mitochondrial protein acetylation and metabolism. Mol Cell 2019;75(4):823 34 e5. [106] He J, Cheng J, Wang T. SUMOylation-mediated responseto mitochondrial stress. Int J Mol Sci 2020;21(16):5657.

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6 Sirtuins in immunometabolism Hongxiu Yu Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China O U T L I N E 6.1 Brief introduction of immunometabolism

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6.1 Brief introduction of immunometabolism Metabolism fuels all cellular processes, ranging from development, proliferation, differentiation, and the effector functions [1]. First, uptake and utilization of nutrients provides the substrates for adenosine triphosphate (ATP) synthesis to sustain various cellular programs. Second, it provides the building blocks for the synthesis of macromolecules, such as RNA, DNA, proteins, and membranes, that are necessary for the proliferation and function of cells. Besides maintaining homeostasis, the immune system senses and defends against pathogens for the life of the organism. These diverse functions are energetically expensive [2]. For instance, the sensing of a pathogen or environmental threats results in the secretion of inflammatory cytokines and chemokines by the innate immune cells and the clonal expansion of adaptive immune cells. Because immune cells lack significant stores of nutrients, they will dramatically increase the uptake of glucose, amino acids, and fatty acids from their microenvironment [3]. The processes require precise control of cellular metabolic pathways [4,5]. Following the entry of glucose into cells via glucose transporters, glucose is metabolized by the interconnected pathways of glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). The glycolysis occurs in the cytoplasm, whereas the latter two are restricted to the mitochondria. Glucose is firstly phosphorylated to glucose 6-phosphate (G-6-P) by hexokinases. During glycolysis, G-6-P is metabolized to pyruvate, reducing nicotinamide adenine dinucleotide (NAD1) to NADH and generating ATP. In hypoxia, pyruvate is reduced to lactate, restoring NAD1 levels in the cell. In normoxia, pyruvate is metabolized to acetyl-coenzyme A (acetyl-CoA), which is oxidized in the TCA cycle to generate NADH. In the redox reactions of OXPHOS, electrons are sequentially transferred to generate a H1 gradient across the inner mitochondrial membrane and to generate ATP. In contrast to glycolysis, mitochondrial OXPHOS is a highly efficient form of generating ATP. Besides glucose metabolism, immune cells utilize three additional pathways—the pentose phosphate pathway (PPP), glutaminolysis, and fatty acid oxidation (FAO)—to meet their functional demands [6,7]. Recently, amino acid metabolism has also been proved to have an important role in controlling immune cells function [811]. The metabolism is integrated to determine the immune cells’ ability to divide, differentiate, and carry out effector functions in immune response [12]. Cellular metabolism plays important roles in regulating acute and chronic inflammation, which involves both innate and adaptive immune cells [13,14]. During the early stage of acute inflammation, such as sepsis, a high

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amount of energy is required and provided by glycolysis. Increased glucose uptake, PPP activation, and glycolysis lead to lactic acid accumulation. Moreover, this initial defensive pathway rapidly becomes toxic to cells by generating excessive reactive oxygen species (ROS) and prompting cell death pathways. Septic patients are likely to spend less than a day, or only a few hours, in the cytokine storm of hyperinflammation. Then the acute systemic inflammation with sepsis will switch to hypoinflammation or adaptation phase [15]. The later stage of acute inflammation is a low-energy response. Fatty acid enters mitochondria and generates acetyl-CoA, which undergoes the TCA cycle to provide NADH as a reducing agent for oxygen support of ATP generation. An increase in ATP production by mitochondrial OXPHOS occurs. Chronic inflammation such as hyperlipidemia, diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD) are associated with altered immune cell metabolism and ineffective immunity [16]. For instance, lipid accumulation in adipose tissue promotes the proinflammatory state of macrophages, further exacerbating obesity-related adipose tissue inflammation [17]. Insulin itself might promote T cell activation through its ability to enhance glucose uptake, amino acid transport, lipid metabolism, and protein synthesis [18]. Different immune cell functions are associated with distinct metabolic configurations [19,20]. Generally, quiescent immune cells rely primarily on FAO and the TCA cycle coupled with OXPHOS to generate ATP. Activated immune cells use glycolysis to generate biomass and ATP [21]. Macrophages are the first line of defense against pathogens and injury and are necessary for the maintenance of tissue homeostasis [22]. Macrophages have been classified into classically activated macrophages (M1) and alternatively activated macrophages (M2). Whereas lipopolysaccharide (LPS) and interferon-γ (IFN-γ) drive M1 macrophage activation, interleukin-4 (IL-4) and IL-13 polarize macrophages to the alternative M2 state [23]. M2 macrophages use fatty acid primarily derived from acquired triacyglycerols to support OXPHOS, and have an intact TCA cycle. M1 macrophages involve an increase in glycolysis, while the TCA cycle is fragmented in cells. Dendritic cells (DCs) are antigen-presenting cells (APC) that critically influence decisions about immune activation or tolerance [24]. Impaired DC function is at the core of common chronic disorders. Knowledge of the mechanisms regulating DC function is necessary to understand the immune system and to prevent disease and immunosenescence. There are four major subsets of DCs: conventional DCs (cDCs), Langerhans cells, monocyte-derived DCs, and plasmacytoid DCs (pDCs). These cells are related to each other as they have a common myeloid progenitor. The development of DCs from progenitor cells is associated with mitochondrial biogenesis. Immature DCs use FAO as a core metabolic process. Activation of DCs leads to a rapid increase in flux through glycolysis and the associated PPP, with an accompanying increase in fatty acid synthesis [25,26]. Once triggered to secrete antibodies, activated B cells are glycolytic. However, the detailed metabolic profiles of differentiated and memory B cells remain to be explored. T cells are the central players in the adaptive immune response. They have evolved to rapidly respond to invading pathogens. The T cell metabolic machinery is regulated for coordination of the transitions in different phases from initial cell growth, massive clonal expansion and differentiation, a contraction or death phase, to the maintenance of immune memory [27,28]. During the initial growth phase, T cells switch from the FAO in naive T cells to the glycolytic, pentose phosphate and glutaminolytic pathways in activated T cells [29]. Furthermore, activated T cells can differentiate into different functional T cell subsets depending on the cytokines and other extracellular signals. These subsets determine the nature of the immune response. Whereas CD81 T cells differentiate into cytotoxic T lymphocytes that kill host cells infected with pathogens, CD41 T cells can differentiate into an effector T cell (Th1, Th2, Th9, or Th17) that mediate appropriate immune responses or induced regulatory T cells (iTreg cells) that suppress uncontrolled immune responses [30,31]. At the end of an immune response, the majority of effector T cells undergo apoptosis, whereas a small percentage persist as memory T cells (Tmem cells), which are responsible for enhanced immunity after reexposure to the pathogen. Of these various T cell subsets, the Tmem cells and iTreg cells rely on oxidizing fatty acid to support OXPHOS, whereas cytotoxic T lymphocytes and effector T cells sustain high glycolytic activity and glutaminolytic activity [32,33]. Glycolysis allows the efficient translation of mRNAs encoding effector cytokines, such as IFN-γ. In terms of metabolic requirements, effector T cells are similar to oncogenically transformed cells [34]. The metabolic signals including extracellular nutrient environment or intracellular metabolic status of immune cells are sensed and transduced to affect cell cycle, differentiation, cell death, and immunological functions. Such signals include metabolites involved in cell metabolic pathways or metabolic products, by-products, and cofactors such as ATP, NAD1-NADH, nicotinamide adenine dinucleotide phosphate (NADP1)-NADPH, acetyl-CoA, and ROS [29,35]. The sensors are cell-surface receptors or transporters that physically interact with and respond to metabolic signals by changes in their biological status. The physical interactions among metabolic signals and sensors trigger a series of intracellular signaling events that result in immune cell differentiation and activation [36].

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Sirtuins, prolyl-4-hydroxylase (PHD) proteins, adenosine 50 -monophosphate (AMP)-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), pyruvate kinase M2 (PKM2), and hypoxia-induced factor 1α (HIF-1α) are central players in the coordinated sensing of cellular metabolic signal and dictation of cell fate [3741]. Furthermore, every step of metabolic signal transduction in immune cells can be modulated, which in turn result in changes in their functional properties [42]. For instance, either pharmacological activation of AMPK or T cell-specific deletion of mTOR is sufficient to drive T cell differentiation toward iTreg cells after antigen stimulation [43,44]. When glycolysis is inhibited by modulation of PKM2 [45], macrophages undergo a shift toward a more M2 macrophage-like state. A similar effect is observed in Th17 cells, which become more like Treg cells if glycolysis is inhibited [40]. This plasticity of immune cells is important. For example, the metabolic reprogramming of immune cells from an inflammatory to an antiinflammatory phenotype or vice versa can be used as a strategy to boost antitumor immunity or inhibit hyperimmune response. Immune cell metabolism has therefore become an attractive target area for therapeutic purposes [46,47].

6.2 Role of sirtuins in immunometabolism The mammalian sirtuins are a family of NAD1-dependent deacetylases and consist of seven members (SIRT1SIRT7) [48]. Sirtuins display a cell type-dependent manner of subcellular localization and biological functions [49]. SIRT1 and SIRT2 shuttle between the nucleus and cytoplasm. SIRT35 mainly localize in mitochondria, while SIRT6 is found exclusively in the nucleus. SIRT7 is found in both the nucleus and cytoplasm. Substrates of sirtuins include histones and nonhistone proteins such as nuclear transcription factors and the key enzymes involved in glycolysis, FAO, the TCA cycle, and other oxidative and metabolic pathways [50]. Although deacetylase activity was initially reported to be conserved in mammalian sirtuins, different sirtuins exhibit different acyl group preferences [51]. Among the seven members, SIRT47 exhibit weak or undetectable deacetylation activity. SIRT2 has efficient demyristoylase activity [52]. SIRT5 is lysine desuccinylase, deglutarylase, and demalonylase [53,54], while SIRT4 and SIRT6 possess ADP-ribosyltransferase activity [55,56]. Because sirtuins are expressed throughout the body, NAD1 is rate-limiting for sirtuins enzymatic reactions, and as a result, sirtuins serve as metabolic sensors of intracellular NAD1 and the redox state [57,58]. Although much are known about the sirtuins in metabolism, the effect of sirtuins on immune cell function and metabolic configuration have not been systematically explored. In this chapter, sirtuins’ functions in immune response and immunometabolism will be discussed. The main findings discussed in the present chapter are summarized in Table 6.1.

6.2.1 SIRT1 6.2.1.1 SIRT1 in macrophage SIRT1 is the most studied family member among sirtuins. Accumulated evidence shows the important role of SIRT1 in immune cell function and immune response. Yoshizaki et al. showed the antiinflammatory role of SIRT1 in macrophages [59]. Knockdown of SIRT1 in the mouse macrophage RAW264.7 cell line and in intraperitoneal macrophages increases intracellular inflammatory c-Jun N-terminal kinase (JNK) and IκB kinase (IKK) pathways, and inflammatory gene tumor necrosis factor alpha (TNF-α) expression. Activated SIRT1 in macrophages restrains proinflammatory responses. SIRT1 activator treatment of Zucker fatty rats leads to glucose tolerance, insulin sensitivity, and reduced tissue inflammatory responses. These in vitro and in vivo results raise the possibility that macrophage SIRT1 may play a beneficial role in regulating the inflammatory component of metabolic diseases. Consistently, Schug et al. have demonstrated that SIRT1 plays a key role in regulating the inflammatory and immune responses in mice [60]. Using a myeloid cell-specific Sirt1 knockout (Mac-Sirt1 KO) mouse model and bone marrow-derived macrophages (BMDMs), they have showed that deletion of SIRT1 in macrophages leads to the components of the nuclear factor kappa B (NF-κB) pathway being hyperacetylated, resulting in increased expression of IL-6 and IL-1β genes. Mac-Sirt1 KO mice challenged with a high-fat diet (HFD) display high levels of activated macrophages in liver and adipose tissue, predisposing mice to the development of insulin resistance and metabolic disorders. This work provides both in vitro and in vivo evidence as to how SIRT1 functions in macrophages or systemically. Furthermore, they also demonstrated that the SIRT1 homolog SIRT6 has a compensatory effect on NF-κB activation in Mac-Sirt1 KO BMDMs.

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TABLE 6.1 Sirtuins function in immnue cells. Gene Immunue cells

Model

Target

Function

References

SIRT1 Macrophage

SIRT1 knockdown RAW264.7 cell

JNK, IKK pathway

Antiinflammation

[59]

Macrophage

Myeloid-specific-Sirt1 KO mouse

NF-κB

Antiinflammation

[60]

Macrophage

Phagocytosis

AP-1

Antiinflammation

[61]

Macrophage

Myeloid-specific-Sirt1 KO mouse

Proinflammation

[62]

Macrophages and adipocyte

Myeloid-specific-Sirt1 KO mouse and Adipocyte-specific-Sirt1 KO mouse

Antiinflammation

[63]

THP-1 promonocyte

Sepsis

PGC-1α

Supports FAO

Inflammation homestasis

[64]

Myeloid-derived suppressor cell

Myeloid-specific-Sirt1 KO mouse

mTOR, HIF-1α

Inhibits glycolysis

Inhibits tumor growth

[65]

Dendric cell

DC-specific-Sirt1 KO mouse

PPAR-γ

Antiinflammation

[66]

Dendric cell

DC-specific-Sirt1 KO mouse

HIF-1α

T cell differention

[67]

CD4 T cell

Sirt1 KO mouse

AP-1

Inhibits autoimmunity

[68]

Th9 cell

CD4-specific-Sirt1 KO mouse

mTOR, HIF-1α

1

CD81 memory T cell

Inhibits glycolysis

Antiallergic [69] airwayInflammation, promotes tumor growth

Inhibits glycolysis

T cell differention

[70]

Inhibits glycolysis

Inhibits phagocytosis by macrophages

[71]

SIRT2 Macrophage

Sirt2 KO mouse

Macrophage

Sirt2 KO mouse

NF-κB

Proinflammation

[72]

Macrophage

Sirt2 KO mouse

NF-κB

Antiinflammation

[73]

SIRT5 Macrophage

Sirt5 KO mouse

NF-κB

Proinflammation

[74]

No effect on infection

[75]

Macrophages

Sirt5 KO mouse

Macrophage

Sirt5 KO mouse

PKM2

Inhibits glycolysis

Antiinflammation

[76]

Sepsis

HIF-1α

Represses glucose metabolism

Inflammation homestasis

[64]

SIRT6 THP-1 promonocyte CD41 T cells, macrophage

Sirt6 KO mouse, T cell-specific and myeloid-specific Sirt6 KO mouse

[77]

Dendric cell

Sirt6 KO mouse

[78]

In addition, SIRT1 deacetylates activator protein-1 (AP-1) to improve macrophage function [61]. AP-1 is a transcription factor, binding to the promoters of the target gene to modulate their expression, which is in turn involved in cell proliferation, differentiation, and inflammation. Cyclooxygenase-2 (COX-2) is the rate-limiting enzyme for prostaglandin (PG) production. Macrophage-derived excessive PGE2 inhibits the phagocytosis activity of macrophages. Zhang et al. have proved SIRT1 deacetylates AP-1 to repress its transcriptional activity and inhibit COX-2 expression and PGE2 production in macrophages, resulting in improved macrophage phagocytosis. In 2015 Ka et al. provided in vitro evidence that myeloid SIRT1 plays a crucial role in macrophage polarization and chemotaxis [62]. Pancreatic islets, liver, and adipose tissues from Sirt1 KO HFD mice show increased macrophages infiltration and tissue inflammation. Sirt1 KO mice fed a HFD exhibit glucose intolerance, reduced insulin secretion, and insulin sensitivity with a slight decrease in body weight. The metabolic phenotype is in contrast to those from the study by Schug et al. [60], in which Sirt1 KO mice exhibit greater weight gain and adipose tissue mass. The author said these opposite results may result from differences in the diet composition.

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Considering the dynamic interplay between adipocytes and macrophages within adipose tissue during the pathogenesis of obesity, Hui et al. have generated adipocyte and myeloid cell-specific Sirt1 KO mice and compared the metabolic phenotypes of them [63]. Compared to myeloid-selective Sirt1 depletion, mice with adipocyte-specific deletion of Sirt1 are more susceptible to diet-induced insulin resistance. Mechanistically, the phenotype in adipocyte specific Sirt1 KO mice is associated with an increased macrophage infiltration into adipose tissues and their polarization toward M1 macrophage. In 2012 Liu et al. provide evidence that SIRT1 and SIRT6 can directly regulate immune cell metabolism [64]. In acute immune responses, the THP-1 promonocytes prefer to use glycolysis to provide high energy, which is sustained by the HIF-1α and NF-κB pathway. As the early inflammatory response changes to late adaptation, glucose metabolism switches to FAO. SIRT1 and SIRT6 integrate sequential reprogramming of metabolic and acute inflammatory responses. SIRT1 supports FAO by activating the peroxisome proliferator-activated receptor-coactivator 1-α (PGC-1α) pathway; SIRT6 represses glucose metabolism by epigenetically silencing the HIF-1α pathway. 6.2.1.2 SIRT1 in myeloid-derived suppressor cells In other innate immune cells, SIRT1 also plays important roles. For example, SIRT1 directs the differentiation of myeloid-derived suppressor cells (MDSCs) [65]. MDSCs are one of the major components of the immunosuppressive network responsible for immune cell tolerance in cancer [79]. Polarized MDSCs lineages can be distinguished as M1 and M2 cells. Liu et al. found that SIRT1 deficiency in MDSCs directs a specific switch to M1 lineage, in favor of tumor cell attack. mTOR- and HIF-1α-induced glycolytic activity is required for differentiation determined by SIRT1. 6.2.1.3 SIRT1 in dendritic cells SIRT1 plays an essential role in mediating proinflammatory and metabolic signaling in DCs. DCs are professional APCs required for the initiation of immune responses [80]. In addition to presenting antigens, DC-derived cytokines and chemokines can result in either a proinflammatory or antiinflammatory environment, engaging distinct T-cell differentiation programs on naive CD41 T cells [81]. As shown previously, in response to antigen stimulation, naive CD41 T cells may differentiate into at least five types of effector Th cells, namely Th1, Th2, Th9, Th17, and iTreg cells, which differ from each other in their cytokine secretion profile and function [82]. Th1 induction by DCs is well documented, and rapid progress is being made on Th17 and Treg stimulation. For example, DC-producing IL-12 can support Th1 development, whereas DC-producing IL-10 or transforming growth factor-β (TGF-β1) can support Treg development [83]. However, the molecular mechanisms by which DCs direct Th2 responses remain more elusive. It has been demonstrated that inappropriate Th2 responses are responsible for the development of allergic diseases [84]. Legutko et al. revealed the function of SIRT1 in the regulation of DCs function and Th2 responses. Firstly, they proved that pharmacological inhibition of SIRT1 dampens Th2 responses and subsequent allergic inflammation by interfering with lung DC function in a murine model of antigen-induced airway allergy. Then, by using DCs cell-specific Sirt1 deletion mouse model, they demonstrated that SIRT1 represses the activity of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) in DCs, thereby favoring their maturation toward a pro-Th2 phenotype. Lack of SIRT1 expression in DCs reduces macrophage and eosinophilic lung infiltration in the murine model [66]. Moreover, by using DCs-specific Sirt1-deficient mouse, Liu et al. indicated that SIRT1 is a metabolic checkpoint regulating the differentiation of Th1 and Treg cells through a HIF-1α-dependent and mTOR-independant pathway [67]. By using DCs-specific Sirt1 deletion mice and microbial-induced inflammation model, Liu and colleagues proved that SIRT1 is required for the reciprocal production of IL-12 and TGF-β1 production in DCs as well as the expression of their receptor in responding T cells, resulting in a differential lineage engagement of Th1 and Treg. The study further implicated a metabolic checkpoint in DCs requiring the interplay of SIRT1 and HIF-1α, two metabolic sensors of redox and oxygen states, respectively. 6.2.1.4 SIRT1 in T cells SIRT1 is expressed in all tissues but is abundant in the thymus, particularly in CD41CD81 thymocytes, suggesting an involvement of SIRT1 in T cell development and function. It has been reported that SIRT1 is involved in maintaining T cell tolerance and its expression is induced considerably in anergic T cells [68,85,86]. CD41CD81 thymocytes from Sirt12/2 mice exhibit increased sensitivity to irradiationinduced apoptosis [87]. T cell-specific deletion of Sirt1 substantially promotes the generation and function of Treg cells in vitro and in vivo [88].

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However, neither the metabolic signals upstream of SIRT1 nor the molecular mechanism that mediates the downstream effects of SIRT1 in these contexts are clear. Moreover, Yu et al. have suggested that SIRT1-dependent glycolytic activity is critical for the differentiation of Th9 cells [69]. The authors have checked the expression of SIRT1 in various T cell subsets Th1, Th2, Th17, Treg, and have found that Th9 cells exhibit a lower expression than other cells. Moreover, Th9 cells exhibit more glycolytic activity than other cells. Deficiency of Sirt1 in CD41 T cells increase IL-9 production and glycolysis. Accordingly, ectopic SIRT1 expression in CD41 T cells inhibits IL-9 production and glycolysis. The work further demonstrates that SIRT1-dependent Th9 cells are important in tumor development and allergic airway inflammation by inhibiting the differentiation of Th9 cells in an mTOR-HIF-1α-dependent glycolytic pathway. This work also indicated metabolic reprogramming to be an immunotherapeutic approach in inflammation and cancer. In 2018 Jeng et al. revealed the role of SIRT1 in regulating CD81 memory T cells [70]. Human CD81CD282 T cells are very cytotoxic, producing greater levels of effector molecules, such as granzyme B (GZMB). Jeng et al. found that CD81CD282 T cells have a decreased expression of SIRT1 and an enhanced capacity of glycolysis. Loss of SIRT1 enhances glycolytic capacity and produces much more GZMB. These data suggest SIRT1 is a regulator of human CD81 memory T cell metabolism and activity. The SIRT1 may provide a potential therapeutic intervention to reprogram terminally differentiated memory T cells. In addition to these works, there are several reviews summarizing the role of SIRT1 in immune cells, inflammation, and cancer [15,89].

6.2.2 SIRT2 SIRT2 is involved with numerous processes such as DNA damage, infection, and carcinogenesis. However, the role of SIRT2 in the inflammatory process remains largely unknown. Ciarlo et al. showed that SIRT2 is the most highly expressed sirtuins in myeloid cells, especially macrophages [71]. By comparing Sirt2 KO mice with the control mice, Ciarlo et al. have suggested that Sirt2 deficiency has no major impact on the development of immune cells, including T cells (double negative T cells, single positive T cells, naı¨ve T cells, and memory T cells), B cells (immature and mature B cells), DCs, and Treg cells. Sirt2 deficiency increases phagocytosis by macrophages and protects from chronic staphylococcal infection. Interestingly, the glycolytic activity was higher in Sirt2 KO than wild-type (WT) BMDMs exposed to Staphylococcus aureus AW7. Moreover, when glycolysis BMDMs was inhibited, it significantly reduced the phagocytosis of Staphylococcus aureus AW7. These results have suggested that the metabolic capacity of macrophages may provide a mechanism by which SIRT2 inhibits phagocytosis. Lee et al. have evaluated the effects of SIRT2 in macrophages [72]. They isolated BMDMs from Sirt2 KO and control mice or RAW264.7 macrophage cells. The authors have demonstrated that the deficiency of Sirt2 results in the inhibition of NF-κB activation through reducing the phosphorylation and degradation of IκBa, then exerting an apparently inhibitory effect on the expression of M1-macrophage-related proinflammatory genes. While Sirt2 deficiency has not shown any significant inhibitory effect on M2-macrophage-related genes. Except for phosphorylation, posttranslational modification of the p65 subunit by acetylation is a major aspect of the regulation of NF-κB activity [73]. It has been demonstrated that SIRT2 regulates NF-κB by binding to NF-κB and mediating the deacetylation of NF-κB. In contrast to Lee’s report, Lo Sasso et al. have reported that Sirt2 deficiency promotes M1-macrophage and inhibits M2- macrophage polarization, mimicking a proinflammatory milieu [90]. More specifically, Sirt2 KO mice develop more severe colitis when exposed to the chemical colitis inducer, dextran sulfate sodium (DSS).

6.2.3 SIRT3, SIRT4, and SIRT5 SIRT3, SIRT4, and SIRT5 are mainly localized in mitochondria. They are well described in the literature to coordinate metabolic pathways involved in stress responses, aging, and others. It is noteworthy that whereas mitochondria play a key role in energetic metabolism, except for SIRT5, no direct evidence has been reported for a role of mitochondrial SIRT3 and SIRT4 during inflammation. SIRT5 is one of the least characterized sirtuins. SIRT5 also localizes in the cytoplasm and is ubiquitously expressed in organs. SIRT5 is a weak deacetylase and recent data suggest that SIRT5 primarily is a lysine demalonylase, desuccinylase, and deglutarylase [53,91,92]. SIRT5 desuccinylates and deglutarylates carbamoyl phosphate synthetase 1 (CSP1) to increase ammonia detoxificationm and desuccinylates succinate dehydrogenase (SDH)

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to repress cellular respiration [93,94]. Overall, SIRT5 is emerging as a key regulator of metabolism. Emerging evidence has revealed that SIRT5 have a pivotal role in immunometabolism. Interestingly, the role of SIRT5 in inflammation is controversial. Qin and colleagues have shown that Sirt5 deficiency decreases LPS-triggered inflammation in both acute and immunosuppressive phases of sepsis. Function screening have revealed that SIRT5 and SIRT1/2 have opposite expression patterns and functions in macrophages [74]. In response to stimulation with LPS, Sirt5 KO peritoneal macrophages produce less proinflammatory cytokines (IL-6 and TNF-α) than control macrophages. Sirt5 deficiency protects mice from endotoxin tolerance. Moreover, SIRT5 counteracts the inhibitory effects of SIRT2 and enhances the inflammatory responses in macrophages by activation of the NF-κB pathway. By using a different genomic background Sirt5 KO mice, Heinonen et al. have showed that Sirt5 deficiency does not affect IL-6 and TNF-α production and proliferation by macrophages [75]. Sirt5 deficiency does not affect the major T cells, B cells, and DCs subsets development. Moreover, Sirt5 deficiency does not worsen endotoxemia and bacterial infection. Wang and colleagues provided evidence that SIRT5 targets PKM2 to protect mice from DSS-induced colitis [76]. PKM2, which catalyzes the rate-limiting step of glycolysis [95], can regulate HIF-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages [41]. The tetramer of PKM2 has a high pyruvate kinase activity, and localizes mainly in the cytosol, whereas dimeric PKM2 preferentially localizes in the nucleus and has a high protein kinase activity. In this work, Sirt5 deficiency leads to increased glycolysis, hypersuccinylation, and dimerization of PKM2 in BMDMs. The dimeric PKM2 in the nucleus directly interacts with HIF-1α and promotes the HIF1α-dependent gene expression, notably IL-1β. This will have an important consequence for the DSS-induced colitis in mice. The study therefore identifies SIRT5 as an important negative regulator of glycolysis in macrophages.

6.2.4 SIRT6 Consistent with previously mentioned works [64], SIRT6 is emerging as an important regulator of glucose metabolism [96]. Sirt6 knockout mice die by severe hypoglycemia and persistent inflammation. SIRT6 has been further proved to have a role in chronic liver inflammation and dendritic cells development. Xiao et al. have provided evidence to show that compared to global Sirt6 KO mice, deletion of Sirt6 in T cells or myeloid-derived cells is sufficient to induce liver inflammation and fibrosis [77]. This result suggests that Sirt6 deficiency in the immune cells is the cause. Consistently, macrophages derived from the bone marrow of Sirt6 KO mice show increased IL-6 and TNF-α expression levels and are hypersensitive to LPS activation. By inhibiting c-JUN-dependent expression of proinflammatory genes, SIRT6 has been shown to play an antiinflammatory role in mice. Lasiglie shows that SIRT6 stimulates the development of myeloid, conventional DCs (cDCs) [78]. Sirt6 KO mice exhibit low frequencies of bone marrow cDCs precursors and low yields of bone marrow-derived cDCs compared to WT animals. Moreover, Sirt6 KO cDCs show a decrease of IL-12, TNF-α, and IL-6 production, which means reduced SIRT6 activity may contribute to immunosenescence.

6.2.5 SIRT7 SIRT7 is the last studied among the seven mammalian sirtuins. SIRT7 is an important regulator of rRNA and protein synthesis for maintenance of normal cellular homeostasis. Vakhrusheva et al. showed that in Sirt7 KO mice, the SIRT7 disruption predisposes the mice to heart hypertrophy together with increasing cardiac inflammation [97]. These authors observed an increased infiltration of immune cells, with higher levels of pro- and antiinflammatory cytokine production. These results suggest that SIRT7 is also involved in inflammation. Information regarding the possible involvement of SIRT7 in inflammatory signaling pathways and mechanisms are still needed.

6.3 Conclusion and future considerations The sirtuins have been implicated in a variety of biological processes including cell cycle progression, apoptosis, cellular senescence, stress response, neuronal protection, adaptation to caloric restriction, metabolism, and tumorigenesis. In addition, accumulated evidence has shown that sirtuins integrate metabolism, bioenergetics, and immunity during inflammation. Moreover, many independent studies regarding the same sirtuin could exert

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Fatty acid

Glucose

FIGURE 6.1 Metabolic control of sirtuins in immune cells. Metabolic signals are sensed by sirtuins, resulting in the activation of distinct signaling pathways to initiate the adaptations of immune cells.

Insulin

SIRT1,2,5,6 mTOR

IKK NFκB JNK

HIF-1α PKM2

AP-1

PGC-1α

c-JUN

PPAR-γ

IL-1β,TNF-α,IL-6,IL-9 Glucose metabolism Fatty acid oxidation

Macrophage

DC

MDSC

T-cell

proinflammation or antiinflammation, indicating that regulation of the inflammatory response by sirtuins is subtler than previously thought. Furthermore, sirtuins’ effects on inflammation can be a double-edged sword, for instance, low levels accentuate early acute inflammation-related autotoxicity by increasing NF-κB activity, and prolonged increases in SIRT1 during late inflammation are associated with immunosuppression and increased mortality [21]. Better understanding of sirtuins’ role in regulation of inflammation and immumetabolism is in its infancy. Except for SIRT1, other sirtuin family members’ roles in immunometabolic reprogramming are largely unknown. SIRT7 in particular is abundant in immune organs. Many works focus on the glucose and fatty acid metabolism regulated by sirtuins. Amino acid abundance and composition may serve as a quality control checkpoint in immune cells [8,37], and more attention should be paid to amino acid metabolism. The architectural principles for the metabolic control of sirtuins in immune cells are shown in Fig. 6.1.

References [1] Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011; 11(5):32537. [2] Ganeshan K, Chawla A. Metabolic regulation of immune responses. Annu Rev Immunol 2014;32(32):60934. [3] Mathis D, Shoelson SE. Immunometabolism: an emerging frontier. Nat Rev Immunol 2011;11(2):81. [4] Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. Immunity 2015;42(3):40617. [5] O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol 2016;16(9):55365. [6] Nagy C, Haschemi A. Time and demand are two critical dimensions of immunometabolism: the process of macrophage activation and the pentose phosphate pathway. Front Immunol 2015;6:164. [7] Mak TW, Grusdat M, Duncan GS, et al. Glutathione primes T cell metabolism for inflammation. Immunity 2017;46(6):108990. [8] Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 2013;14(5):5008. [9] Ron-Harel N, Santos D, Ghergurovich JM, et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab 2016;24(1):10417. [10] Geiger R, Rieckmann JC, Wolf T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016;167(3):82942 e813. [11] Rodriguez AE, Ducker GS, Billingham LK, et al. Serine metabolism supports macrophage IL-1beta production. Cell Metab 2019; 29(4):100311 e1004. [12] Norata GD, Caligiuri G, Chavakis T, et al. The cellular and molecular basis of translational immunometabolism. Immunity 2015; 43(3):42134. [13] Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. Nat Med 2009; 15(5):4967. [14] Medzhitov R. Origin and physiological roles of inflammation. Nature 2008;454(7203):42835.

I. Sirtuins and metabolic disease

References

99

[15] Vachharajani VT, Liu T, Wang X, Hoth JJ, Yoza BK, McCall CE. Sirtuins link inflammation and metabolism. J Immunol Res 2016;2016:8167273. [16] Odegaard JI, Chawla A. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab 2008;4(11):61926. [17] Prieur X, Mok CY, Velagapudi VR, et al. Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 2011;60(3):797809. [18] Winer DA, Winer S, Shen L, et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 2011;17(5):61017. [19] Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity 2013;38(4):63343. [20] Odegaard JI, Chawla A. The immune system as a sensor of the metabolic state. Immunity 2013;38(4):64454. [21] Murray PJ, Rathmell J, Pearce E. SnapShot: immunometabolism. Cell Metab 2015;22(1) 190190. e191. [22] Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013;496(7446):44555. [23] Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003;3(1):2335. [24] Satpathy AT, Wu X, Albring JC, Murphy KM. Re(de)fining the dendritic cell lineage. Nat Immunol 2012;13(12):114554. [25] Pearce EJ, Everts B. Dendritic cell metabolism. Nat Rev Immunol 2015;15(1):1829. [26] O’Neill LAJ. Glycolytic reprogramming by TLRs in dendritic cells. Nat Immunol 2014;15(4):31415. [27] Schumacher TN, Gerlach C, van Heijst JW. Mapping the life histories of T cells. Nat Rev Immunol 2010;10(9):62131. [28] Zeng H, Chi HB. Metabolic control of regulatory T cell development and function. Trends Immunol 2015;36(1):312. [29] Wang RN, Green DR. Metabolic checkpoints in activated T cells. Nat Immunol 2012;13(10):90715. [30] Zhou L, Chong MM, Littman DR. Plasticity of CD4 1 T cell lineage differentiation. Immunity 2009;30(5):64655. [31] Harty JT, Badovinac VP. Shaping and reshaping CD8 1 T-cell memory. Nat Rev Immunol 2008;8(2):10719. [32] van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD81 T cell memory development. Immunity 2012;36(1):6878. [33] Xu T, Stewart KM, Wang X, et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 2017; 548(7666):22833. [34] Chang CH, Curtis JD, Maggi Jr. LB, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013; 153(6):123951. [35] Menzies KJ, Zhang HB, Katsyuba E, Auwerx J. Protein acetylation in metabolism - metabolites and cofactors. Nat Rev Endocrinol 2016;12(1):4360. [36] Wellen KE, Thompson CB. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol 2012;13(4):2706. [37] Nakaya M, Xiao Y, Zhou X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 2014;40(5):692705. [38] Zeng H, Cohen S, Guy C, et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 2016;45(3):54054. [39] Blagih J, Coulombe F, Vincent EE, et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 2015;42(1):4154. [40] Shi LZ, Wang R, Huang G, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011;208(7):136776. [41] Palsson-McDermott EM, Curtis AM, Goel G, et al. Pyruvate kinase M2 regulates Hif-1 alpha activity and IL-1 beta induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab 2015;21(1):6580. [42] DuPage M, Bluestone JA. Harnessing the plasticity of CD4(1) T cells to treat immune-mediated disease. Nat Rev Immunol 2016; 16(3):14963. [43] Michalek RD, Gerriets VA, Jacobs SR, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4(1) T cell subsets. J Immunol 2011;186(6):3299303. [44] Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009;30(6):83244. [45] Palsson-McDermott EM, Curtis AM, Goel G, et al. Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab 2015;21(1):6580. [46] Jung J, Zeng H, Horng T. Metabolism as a guiding force for immunity. Nat Cell Biol 2019;21(1):8593. [47] Zmora N, Bashiardes S, Levy M, Elinav E. The role of the immune system in metabolic health and disease. Cell Metab 2017;25(3):50621. [48] Hirschey MD. Old enzymes, new tricks: sirtuins are NAD(1)-dependent de-acylases. Cell Metab 2011;14(6):71819. [49] Nakagawa T, Guarente L. SnapShot: sirtuins, NAD, and aging. Cell Metab 2014;20(1) 192192. e191. [50] Shakespear MR, Iyer A, Cheng CY, et al. Lysine deacetylases and regulated glycolysis in macrophages. Trends Immunol 2018; 39(6):47388. [51] Rauh D, Fischer F, Gertz M, et al. An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms. Nat Commun 2013;4:2327. [52] Teng YB, Jing H, Aramsangtienchai P, et al. Efficient demyristoylase activity of SIRT2 revealed by kinetic and structural studies. Sci Rep 2015;5:8529. [53] Du J, Zhou Y, Su X, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 2011;334(6057):8069. [54] Tan MJ, Peng C, Anderson KA, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 2014;19(4):60517. [55] Haigis MC, Mostoslavsky R, Haigis KM, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006;126(5):94154. [56] Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 2005; 280(22):2131320.

I. Sirtuins and metabolic disease

100

6. Sirtuins in immunometabolism

[57] Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403(6771):795800. [58] Smith BC, Hallows WC, Denu JM. A continuous microplate assay for sirtuins and nicotinamide-producing enzymes. Anal Biochem 2009;394(1):1019. [59] Yoshizaki T, Schenk S, Imamura T, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab 2010;298(3):E41928. [60] Schug TT, Xu Q, Gao H, et al. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol 2010;30(19):471221. [61] Zhang R, Chen HZ, Liu JJ, et al. SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J Biol Chem 2010;285(10):7097110. [62] Ka SO, Song MY, Bae EJ, Park BH. Myeloid SIRT1 regulates macrophage infiltration and insulin sensitivity in mice fed a high-fat diet. J Endocrinol 2015;224(2):10918. [63] Hui X, Zhang M, Gu P, et al. Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue. EMBO Rep 2017;18(4):64557. [64] Liu TF, Vachharajani VT, Yoza BK, McCall CE. NAD 1 -dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J Biol Chem 2012;287(31):2575869. [65] Liu G, Bi Y, Shen B, et al. SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1alphadependent glycolysis. Cancer Res 2014;74(3):72737. [66] Legutko A, Marichal T, Fievez L, et al. Sirtuin 1 promotes Th2 responses and airway allergy by repressing peroxisome proliferatoractivated receptor-gamma activity in dendritic cells. J Immunol 2011;187(9):451729. [67] Liu G, Bi Y, Xue L, et al. Dendritic cell SIRT1-HIF1alpha axis programs the differentiation of CD4 1 T cells through IL-12 and TGF-beta1. Proc Natl Acad Sci U S A 2015;112(9):E95765. [68] Zhang J, Lee SM, Shannon S, et al. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J Clin Invest 2009;119(10):304858. [69] Wang Y, Bi Y, Chen X, et al. Histone deacetylase SIRT1 negatively regulates the differentiation of interleukin-9-producing CD4(1) T cells. Immunity 2016;44(6):133749. [70] Jeng MY, Hull PA, Fei M, et al. Metabolic reprogramming of human CD8(1) memory T cells through loss of SIRT1. J Exp Med 2018; 215(1):5162. [71] Ciarlo E, Heinonen T, Theroude C, et al. Sirtuin 2 deficiency increases bacterial phagocytosis by macrophages and protects from chronic staphylococcal infection. Front Immunol 2017;8:1037. [72] Lee AS, Jung YJ, Kim D, et al. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages. Biochem Biophys Res Commun 2014;450(4):13639. [73] Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci 2010;123(Pt 24):42518. [74] Qin K, Han C, Zhang H, Li T, Li N, Cao X. NAD(1) dependent deacetylase Sirtuin 5 rescues the innate inflammatory response of endotoxin tolerant macrophages by promoting acetylation of p65. J Autoimmun 2017;81:1209. [75] Heinonen T, Ciarlo E, Theroude C, et al. Sirtuin 5 deficiency does not compromise innate immune responses to bacterial infections. Front Immunol 2018;9:2675. [76] Wang F, Wang K, Xu W, et al. SIRT5 desuccinylates and activates pyruvate kinase M2 to block macrophage IL-1 beta production and to prevent DSS-induced colitis in mice. Cell Rep 2017;19(11):233144. [77] Xiao C, Wang RH, Lahusen TJ, et al. Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice. J Biol Chem 2012;287(50):4190313. [78] Lasiglie D, Boero S, Bauer I, et al. Sirt6 regulates dendritic cell differentiation, maturation, and function. Aging (Albany NY) 2016; 8(1):3449. [79] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9(3):16274. [80] Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767811. [81] Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol 2010;11(8):67480. [82] Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 2008;112(5):155769. [83] Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008;453(7192):23640. [84] Paul WE, Zhu J. How are T(H)2-type immune responses initiated and amplified? Nat Rev Immunol 2010;10(4):22535. [85] Gao B, Kong Q, Kemp K, Zhao YS, Fang D. Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2-mediated reversal of T-cell tolerance. Proc Natl Acad Sci U S A 2012;109(3):899904. [86] Sequeira J, Boily G, Bazinet S, et al. sirt1-null mice develop an autoimmune-like condition. Exp Cell Res 2008;314(16):306974. [87] Cheng HL, Mostoslavsky R, Saito S, et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A 2003;100(19):107949. [88] Beier UH, Wang L, Bhatti TR, et al. Sirtuin-1 targeting promotes Foxp3 1 T-regulatory cell function and prolongs allograft survival. Mol Cell Biol 2011;31(5):10229. [89] Preyat N, Leo O. Sirtuin deacylases: a molecular link between metabolism and immunity. J Leukoc Biol 2013;93(5):66980. [90] Lo Sasso G, Menzies KJ, Mottis A, et al. SIRT2 deficiency modulates macrophage polarization and susceptibility to experimental colitis. PLoS One 2014;9(7):e103573. [91] Rardin MJ, He W, Nishida Y, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 2013; 18(6):92033. [92] Tan M, Peng C, Anderson KA, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 2014;19(4):60517.

I. Sirtuins and metabolic disease

References

101

[93] Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell. 2009;137(3):56070. [94] Zhou L, Wang F, Sun R, et al. SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep 2016;17(6):81122. [95] Christofk HR, Vander Heiden MG, Harris MH, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008;452(7184):2303. [96] Zhong L, D’Urso A, Toiber D, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010;140(2):28093. [97] Vakhrusheva O, Smolka C, Gajawada P, et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res 2008;102(6):70310.

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C H A P T E R

7 Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation Maja Grabacka1 and Przemyslaw M. Plonka2 1

The Department of Biotechnology and General Technology of Foods, Faculty of Food Technology, University of Agriculture in Krako´w, Krako´w, Poland 2The Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, The Jagiellonian University in Krako´w, Krako´w, Poland O U T L I N E Abbreviations

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7.10 The interplay between Sirt3 and isocitrate dehydrogenase in cancer cells

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7.11 Tumor-suppressing and tumor-promoting activities of sirtuins in the context of glutamine and glucose metabolism

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7.12 Sirtuins regulate ironsulfur cluster assemblage

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7.1 Introduction—advantages of possessing mitochondria

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7.2 Mitochondrial sirtuins

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7.3 Lipoylation of multienzymatic complexes is essential for mitochondrial metabolism

106

7.4 Alternative lipoylation and its metabolic consequences

109

7.5 Regulation of pyruvate dehydrogenase complex by mitochondrial sirtuins

110

7.13 Mitochondrial fatty acid synthesis is linked to FeS cluster assembly and protein lipoylation—implications for cancer cell metabolism

7.6 Alpha ketoglutarate dehydrogenase complex regulates gene expression

111

7.14 Consequences of FeS cluster defects in cancer cells

118

7.7 Fluctuations of the intracellular concentration of organic acids has far-reaching implications

112

7.15 Deoxyribonucleotide synthesis—toward the as yet unexplored areas of sirtuin research

119

7.8 Ketogenic enzymes ACAT1 and HMGCS2 as substrates for Sirt3 and Sirt5

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7.16 Perspectives—evolutionary implications and new directions in cancer treatment

120

7.9 Antagonistic roles of mitochondrial sirtuins in fed and fasted state

References

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Sirtuin Biology in Cancer and Metabolic Disease. DOI: https://doi.org/10.1016/B978-0-12-822467-0.00001-2

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© 2021 Elsevier Inc. All rights reserved.

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Abbreviations 2-HG ACADSB ACAT1 ACSM1 aKG AML BCKDC CIA Clp CPT1 D2HGDH DLAT DLD DLST EGF ETC FRDA FXN GAPDH GCS GDH GLS1 GSH GSSG HCC HIF-1α HMGCL HMGCS2 IDH IRP1, IRP2 ISC JmjC KAR1 KAT2A KDM KGDC KGDH L2HGDH LCAD LDH LECA LIAS LIPT1 LIPT2 LYRM mACO MBP MCAT MCCC MCD MDH MECR MEFs MoaA mtACP mtFAS NIF NMP NSCLC OADC OXPHOS OXSM PDC

2-hydroxyglutarate short-branched-chain acyl-CoA dehydrogenase acetyl-CoA acetyltransferase 1 acyl-CoA synthetase medium-chain family member 1 alpha ketoglutarate (2-oxoglutarate) acute myeloid leukemia branched chain ketoacyl-CoA dehydrogenase complex cytosolic ironsulfur cluster assembly caseinolytic peptidase carnitine palmitoyltransferase D-2-hydroxyglutarate dehydrogenase dihydrolipoyl acetyltransferase dihydrolipoyl dehydrogenase dihydrolipoyl succinyltransferase epidermal growth factor electron transfer chain Friedereich ataxia frataxin glyceraldehyde-3-phosphate dehydrogenase glycine cleavage system glutamate dehydrogenase glutaminase 1 glutathione (reduced) glutathione (oxidized) hepatocellular carcinoma hypoxia inducible factor 1 alpha 3-hydroxy-3-methylglutaryl-CoA lyase 3-hydroxy-3-methylglutaryl-CoA synthase 2 isocitrate dehydrogenase iron regulatory proteins 1, 2 mitochondrial ironsulfur cluster assembly Jumonji C domain 3-ketoacyl-ACP reductase lysine acetyltransferase 2A lysine demethylase alpha ketoglutarate (2-oxoglutarate) dehydrogenase complex alpha ketoglutarate (2-oxoglutarate) dehydrogenase L-2-hydroxyglutarate dehydrogenase long chain acyl-CoA dehydrogenase lactate dehydrogenase last eukaryotic common ancestor lipoic acid synthase lipoyltransferase 1 lipoyltransferase 2 Leucine-tyrosine-arginine (LYR) motif containing proteins mitochondrial aconitase methyl-binding domain protein malonyl-CoA:ACP transferase methylcrotonyl-CoA carboxylase complex malonyl-CoA decarboxylase malate dehydrogenase 2-enoly-ACP reductase mouse embryonic fibroblasts molybdenum cofactor biosynthesis protein A mitochondrial acyl-carrier protein mitochondrial fatty acid synthesis nitrogen fixation system nucleotide monophosphate nonsmall cell lung cancer oxoadipate dehydrogenase complex oxidative phosphorylation ketoacyl-ACP synthase pyruvate dehydrogenase complex

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7.1 Introduction—advantages of possessing mitochondria

PDH PDP1 PEP PHD PDK14 PKL PKM PKR PPP Ppt2 RIC RNR ROS SAM SDH SDHA, SDHB SUF TET TfR1 THF VLCAD

105

pyruvate dehydrogenase pyruvate dehydrogenase phosphatase 1 phosphoenolpyruvate prolyl hydroxylase pyruvate dehydrogenase kinases 14 pyruvate kinase L isoenzyme pyruvate kinase M isoenzyme pyruvate kinase R isoenzyme pentose phosphate pathway phosphopantetheine transferase 2 repair of iron clusters ribonucleotide reductase reactive oxygen species S-adenosylmethionine succinate dehydrogenase succinate dehydrogenase subunits A, B sulfur mobilization system ten-eleven translocation transferrin receptor 1 tetrahydrofolate very-long-chain acyl-CoA dehydrogenase

7.1 Introduction—advantages of possessing mitochondria Mitochondria are the organelles of vital importance for the synthesis of key cellular components and the place that integrate various metabolic processes. They carry out respiration, intertwine biosynthesis and degradation of major nutrients, and provide indispensable intermediates for other organelles. The acquisition of mitochondria was undoubtedly one of the most important steps in the eukaryotic evolution, but the exact chronology of the gradual, mutual adaptations of host and endosymbiont, as well as the calculations of the initial costs and benefits of this partnership are a subject of vivid discussions [13]. Nevertheless, the acquisition of mitochondria was crucial, primarily not because of energy generating advantage, but supposedly due to the provision of efficient ironsulfur (FeS) cluster assembly machinery, the mitochondrial ISC (iron sulfur cluster) system. FeS clusters are believed to be one of the most ancient inorganic catalysts, indispensable for life in any form. This notion has been recently challenged by creating a genetically manipulated Escherichia coli strain devoid of ISC and sulfur mobilization (SUF) systems (ultimately lethal), that was able to survive, when the components of the eukaryotic mevalonate pathway synthesizing isoprenoid units were introduced [4]. Nevertheless, it is quite clear that FeS lacking organisms could not compete with optimally equipped counterparts and would be most likely eliminated by natural selection in a real environment. Living organisms developed three enzymatic systems for FeS assembly, namely prokaryotic SUF, nitrogen fixation (NIF), and ISC systems, as well as the eukaryotic cytoplasmic ironsulfur cluster (CIA) system. Mitochondrial ISC machinery is inherited from an alpha proteobacterial endosymbiont. Although it is accepted that the last eukaryotic common ancestor (LECA) surely possessed FeS assembly machinery, it is not yet exactly clear which of the prokaryotic systems supported CIA in LECA [5]. It must be also noted that the first reductases utilizing FeS clusters must emerge as early as in the so-called “RNA World,” because it is hardly possible to imagine deoxyribonucleotide (therefore, DNA) synthesis from ribonucleotides without the participation of such enzymes as ribonucleotide reductases (RNR) [68]. In mammalian cells, FeS clusters are indispensable prosthetic groups for a huge variety of enzymes including respiratory complexes (I, II, III), Krebs cycle enzymes (aconitase, succinate dehydrogenase, fumarase), the enzymes involved in tRNA maturation (TYW1, CDKAL1, CDK5RAP1, ELP3), and DNA replication and repair (RNR, polymerases δ, ε, ζ, primase, helicases, nucleases, DNA glycosylases) [9,10]. The proper assembly of FeS clusters and the transfer to apoproteins is carried out by mitochondrial ISC and cytoplasmic CIA systems. Apart from being the main source of ATP, mitochondria harbor enzymatic machinery for intermediate metabolism and coenzyme biosynthesis (such as lipoic acid or heme, just to mention a few), as well as take part in the maintenance of cellular homeostasis and act as sensors of nutritional status. As a fulfillment of these roles, two main signaling routes between the mitochondrion and the nucleus have evolved: retrograde and anterograde signaling. Anterograde signaling (nucleus to mitochondria) is a consequence of progressive loss of transcriptional and translational autonomy and the increasing number of nuclear-encoded proteins with a final destination in mitochondria. Retrograde signaling (mitochondria to nucleus) provide an important feedback that can prompt

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with rescue and repair actions in the case of defects in mitochondrial function. Efficient nuclearmitochondrial cooperation is a matter of cell survival and in the situations of severe imbalance, mitochondria initiate the pathway to apoptosis. All these necessary functions of mitochondria are performed by a network of proteins, whose activities are finely tuned by numerous posttranslational modifications and allosteric regulation. Mitochondrial sirtuins (Sirt3, Sirt4, and Sirt5) play a crucial role in these processes directly due to their deacylation or ADP-ribosylation activities, or indirectly by regulating the concentration of important metabolites, such as acetyl-CoA, succinyl-CoA, etc.

7.2 Mitochondrial sirtuins Sirtuins have gained much attention in the last two decades, due to their apparent engagement in diverse phenomena, beginning from life span and cell survival, metabolism, and the response to nutritional status. Based on phylogenetic conservation of the core domain, mammalian sirtuins are divided into four subclasses: I—Sirt1, 2, 3 with deacetylase activity; II—Sirt4 with ADP-ribosyltransferase and lipoamidase activity; III—Sirt5 with weak deacetylase and strong desuccinylase, demalonylase and deglutarylase activities; and IV—Sirt6, 7 with both deacetylase and ADP-ribosyltransferase [11]. All sirtuins are NAD-dependent enzymes that cleave this coenzyme producing nicotinamide and 2-O-acyl-ADP ribose derivative. They possess deacylase and/or ADPribosyltransferase activities. In the last 20 years, rapidly emerging discoveries have revealed that acetylation, succinylation, and the other acyl PTMs are much more frequent in the mitochondrial proteome than was previously believed [1214]. The constant progress in sophisticated proteomic analyses and surveys has led to the identification of new amino acid sites, which contribute to enzymatic activity or proteinprotein interactions and can be regulated through acylation. Although protein acylation (especially acetylation and succinylation) is mostly a nonenzymatic process [15], the cleavage of these modifications is entirely enzymatic, executed just by sirtuins. Recently, the mitochondrial sirtuins (Sirt3, 4, 5) have emerged as the key regulators of a global enzymatic activity and metabolic fluxes through various intertwingled pathways carried out in the mitochondria, such as fatty acid oxidation, ketogenesis, the Krebs cycle, respiration, amino acid and pyruvate metabolism. The clear distinction of mitochondrial sirtuins based on their enzymatic activities is somewhat difficult, as some of the catalytic activities overlap (Table 7.1), but generally Sirt3 is regarded as deacetylase that recognizes acylated lysines of neutral charge [39], Sirt4 cleaves negatively charged moieties with branched acyl chain (methylglutaconyl, methylglutaryl, and 3-hydroxy-3-methylglutaryl), as well as biotin and lipoamide [27,29], whereas Sirt5 prefers shorter, unbranched carboxylic acid moieties (succinyl, malonyl, glutaryl) [33,36,37,39]. Multiple mitochondrial proteins are modified by acylation, which has a strong impact on their enzymatic activity. This is a part of feedback response in tuning the enzyme activity. The occupation of acetylation, succinylation, malonylation, and glutarylation sites frequently overlap (Table 7.2), creating an “acylation code” [38]. These modifications executed on lysine residues are mutually exclusive, but the degree of the overlap among the acetylome, succinylome, malonylome, and glutarylome varies depending on the tissue/ cell compartment (e.g., hepatocytes, as compared to embryonic fibroblasts and mitochondria to cytoplasm) and the nutritional status (fed or fasted) [29,38,42]. For example, in mouse embryonic fibroblasts (MEFs), 997 succinylated and 2240 acetylated sites were identified, 282 of which overlap [31]. The majority of modifications are highly prevalent in mitochondria, but some, such as malonylation, are much more frequent in cytoplasmic proteins [38]. Among mitochondrial proteins the degree of overlap between acetylation and succinylation sites reaches 80% [39], nevertheless there are some succinylated proteins present exclusively in cytoplasm or nucleus [31]. Reactive thioesters are the intermediates of all major catabolic pathways, that is, degradation of pyruvate, fatty acids, amino acids, and Krebs cycle components and the diversity in their relative abundance in various tissues might be the main reason for the different patterns in acylome in these tissues [42].

7.3 Lipoylation of multienzymatic complexes is essential for mitochondrial metabolism Lipoylation is a special kind of posttranslational modification that engages lipoic acid attachment to multimeric enzyme complexes of 2-ketoacid dehydrogenases: pyruvate dehydrogenase (PDC), alpha-ketoglutarate dehydrogenase (KGDC), branched chain ketoacyl-CoA dehydrogenase (BCKDC), oxoadipate dehydrogenase (OADC), as well as the glycine cleavage system (GCS). Lipoic acid is a sulfur derivative of octanoic acid

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TABLE 7.1 The enzymatic activities of mitochondrial sirtuins and their selected important target proteins. Mitochondrial sirtuins

EC number

Sirt3

2.3.1.286

Enzymatic activities Deacetylase (Protein N-acetyltransferase)

Decrotonylase Sirt4

2.4.2.30

Selected substrates (References)

Regulated processes/pathways

PDH [16], mACO [17]

TCA

ACS2 [18]

Fatty acid synthesis

ACLY [19]

Fatty acid synthesis

ACAT1 [16,20]

Ketogenesis

HMGCS2 [21]

Ketogenesis

LCAD, VLCAD [22,23]

Fatty acid oxidation

ACADSB [24]

Branched chain amino acid metabolism

OTC [24]

Urea cycle

Histone H3 [25]

Transcription

ADP-ribosyltransferase GDH [26] PDH [27,28]

Lipoamidase

Demethylglutarylase MCCC [29] Demethylglutaconylase De-HMG-ase Deacetylase MCD [30] Sirt5

2.3.1.B43

Glutamine/glutamate metabolism, anaplerosis Acetyl-CoA synthesis Branched chain amino acid catabolism

Fatty acid synthesis /fatty acid oxidation balance

PDH, SDH, IDH [31]

Acetyl-CoA synthesis, TCA

HMGCS2, ACAT1 [32]

Ketogenesis

VLCAD [23], HADHA [31]

Fatty acid oxidation

CPS1 [33]

Urea cycle

GLS1 [34]

Glutaminolysis

PKM2 [35]

Glycolysis

Deglutarylase

CPS1, HADHA [36]

Urea cycle

Demalonylase

CPS1 [37,38]

Urea cycle

Aldolase, GAPDH and other glycolytic enzymes [38]

Glycolysis

Desuccinylase Deacetylase (weak)

The abbreviations of enzyme names are explained in the abbreviations section.

(Fig. 7.1A), synthesized in the FASII mitochondrial fatty acid pathway (mtFAS) and covalently linked to a lysine residue in the evolutionary conservative lipoyl-binding domain, through an amide bond [28]. Lipoamide cofactor is crucial for the redox reactions as it may cyclically form reduced thiol groups (dihydrolipoamide), oxidized disulfide, or a S-adduct with a ketoacid substrate. Lipoamide forms a “swinging arm,” which facilitates the substrate shuttle within the multiprotein complexes and the transfer to coenzyme A (Fig. 7.1B) [43]. These enzymatic complexes have a similar structure that consists of three main components, E1, E2, and E3 (Fig. 7.1B). The E2 component (dihydrolipoyl acetyltransferase, DLAT, in PDC; dihydrolipoyl succinyltransferase, DLST, in KGDC; lipoamide acyltransferase in BCKDC, and protein H in GCS, oxoadipate dehydrogenase complex shares E2 and E3 components with KGDC) possesses lipoamide. E1 components catalyze substrate decarboxylation using thiamine pyrophosphate, E2 components generate acyl-CoA by means of lipoamide reduction to dihydrolipoamide, and the third component E3 regenerates lipoamide by the redox reactions that utilize FAD and NADH coenzymes. Interestingly, the components of all five lipoyl-modified enzyme complexes possess acetylation and succinylation sites targeted by Sirt3 and Sirt5 [31,39,40]. All these enzymatic complexes have a role in the mitochondrial metabolism and are the source of numerous reactive acyl-CoA thioesters: PDC produces acetyl-CoA, a two-carbon unit for sustaining the Krebs cycle; KGDC

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TABLE 7.2 The selected examples of lysine acylome overlapping in the mitochondrial proteins involved in various metabolic pathways. Potential number and type of acylated sites

The particularly important modified lysine residues

Protein

Ac

Suc

Mal

Glu

Carbamoyl phosphate synthase 1 (CPS1)

55

41



43

K55, K219, K412, K892, K915, K1360, K1486

Urea cycle

Ornithine carbamoyltransferase (OTC)

9

11



11

K88

Urea cycle

3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2)

12

15





K83, K310, K447, K473

Ketogenesis

Acetyl-CoA acetyltransferase (ACAT1)

12

12

6

11

K174, K181, K251, K263, K268, K273

Ketogenesis

3-Hydroxyacyl-CoA dehydrogenase (HADH)

11

11



11

K81, K185

Beta oxidation

Trifunctional enzyme, A subunit (HADHA)

25

25



15

K295, K406, K505, K540, K644

Beta oxidation

Very long chain acyl-CoA dehydrogenase (ACADVL)

10

10





K298, K299, K482, K492, K507

Beta oxidation

Succinate dehydrogenase subunit A (SDHA)

18

10

1

13

K179

Krebs cycle, respiration

Malate dehydrogenase 2 (MDH2)

14

14

3

13

K185, K301, K307, K314

Krebs cycle

Malonyl-CoA decarboxylase (MCD)

6

2





K471

Acetyl-CoA synthesis

PDHA (E1 component of Pyruvate dehydrogenase complex (PDC))

5

5





K321

Acetyl-CoA synthesis

Dihydrolipoyl acetyltransferase (DLAT, E2 component of PDC)

1

2





K132, K259—Lipoylated

Acetyl-CoA synthesis

Dihydrolipoyl dehydrogenase (DLD, E3 component of PDC, KGDC, BCKDH)

10

12





K143, K410, K417

Acetyl-CoA synthesis; Krebs cycle, Amino acid metabolism

PDHX (PDC component X)

1

1





K97 lipoylated

Acetyl-CoA synthesis

ATP synthase subunit O

9

6

2

K90, K162

Respiration

Glutamate dehydrogenase (GDH)

24

19

3



Amino acid metabolism

Methylcrotonyl-CoA carboxylase (MCCA)

13

6



4a

K84, K480, K503 C172—ADP-ribosylated K66, K655, K683, K667—biotinylated active site

a Glutaryl moiety derivatives: methylglutaryl-, 3-hydroxy-3-methylglutaryl-, methylglutaconyl- modifications at K66, K432, K490, K501, K677, K691, K692. Yet the significance of PTMs at a particular site and stoichiometry of a given modification, is still to be evaluated (based on [16,2024,29,31,32,37,38,40,41]). Ac, Acetylation; Glu, glutarylation; Mal, malonylation; Suc, succinylation.

Pathway and action

Amino acid metabolism

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FIGURE 7.1 Lipoic acid is a crucial cofactor in the 2-oxoacid dehydrogenase complexes. Pyruvate dehydrogenase serves as an example of such a lipoylated enzyme complex. (A) synthesis of lipoic acid moiety from octanoyl acid, a product of the mitochondrial fatty acid synthesis pathway (mtFAS). Mitochondrial acyl-carrier protein (ACP) provides octanoyl residue, which is transferred to glycine cleavage system component, protein H, by octanoyltransferase (LIPT2). Lipoic acid synthase (LIAS) inserts sulfur atoms from FeS cluster and S-adenosylmetionine (SAM) to form lipoic acid. Lipoate is then transferred by lipoyltransferase LIPT1 from H protein to the lysine residue on the apo-pyruvate dehydrogenase E2 component. (B) Pyruvate dehydrogenase complex consists of three types of subunits: pyruvate dehydrogenase (PDH) E1 that decarboxylates pyruvate to acetyl moiety using thiamine pyrophosphate prosthetic group (TPP); dihydrolipoyl acetyltransferase (DLAT) is a E2 component that employs lipoamide to transfer the acetyl group from TPP to CoA-SH, forming acetyl-CoA; finally dihydrolipoate is oxidized back by dihydrolipoyl dehydrogenase (DLD) E3 component, which is a flavoprotein that uses FAD and NAD as electron acceptors.

produces succinyl-CoA in the Krebs cycle as well; the BCKDC and branched chain amino acid degradation pathway is a source of several acyl-CoAs (isovaleryl, methylbutyryl, isobutyryl), which ultimately generate acetylCoA and succinyl-CoA. The GCS decarboxylates glycine and participates in the methylation of tetrahydrofolate (THF) to form 2,10-methylene-THF, which is an intermediate in the formation of methyl group donors (such as S-adenosylmethionine, SAM). These compounds are necessary for protein and DNA methylation and epigenetic regulation [44]. Importantly, the SAM radical family of enzymes comprises tRNA nucleoside thiolating enzymes (TYW1, ELP3, CDK5RAP1), lipoic acid synthase (LIAS), or molybdenum cofactor biosynthesis protein A (MoaA) [9]. The common feature of these enzymes is the usage of [4Fe4S] clusters during catalysis and cleavage of SAM to 5-adenosyl radical (5-dA*) and methionine [43]. Mammalian lipoic acid biosynthesis and protein lipoylation is linked to mitochondrial fatty acid synthesis (mtFAS). Mitochondrial acyl-carrier protein (mtACP) is especially important in this pathway. mtACP is a donor of the octanoyl chain to octanoyltransferase (LIPT2), which moves the octanoate from ACP to the protein H of GCS. Then LIAS uses its two [4Fe4S] clusters, SAM, and an additional FeS containing scaffold protein to insert two sulfur atoms into the acyl chain and to form lipoic acid moiety [45] (Fig. 7.1A). One of its FeS clusters serves as a sulfur donor and is destroyed during catalysis, but then is reassembled with the help of a FeS donating scaffold protein (see also Section 7.13). Methionine and 5-dA* are released in the reaction, too [43]. The formed lipoic acid is transferred finally from H protein to E2 subunits of 2-ketoacid dehydrogenase complexes by lipoyltransferase LIPT1.

7.4 Alternative lipoylation and its metabolic consequences Recently, a novel mechanism that controls protein lipoylation has been discovered [46]. The polymerase δ-interacting protein 2 (Poldip2) has been shown to regulate lipoylation of PDC and KGDC taking part in the, so-called, salvage pathway. This is a process of exogenous lipoic acid utilization, an alternative to lipoic acid de novo synthesis. The acyl-CoA synthetase medium-chain family member 1 (ACSM1), which participates in this process, activates the absorbed lipoic acid to a nucleotide conjugate, lipoyl-NMP. This enzyme possesses multiple acetylation and succinylation sites recognized by Sirt3 and Sirt5 [31,39,40].

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In mitochondria, Poldip2 binds to CLPX protein, which is a subunit of proteasome-like caseinolytic peptidase (Clp) complex. CLPX acts as an ATP-dependent unfoldase that controls the entry of proteins intended for degradation into the Clp proteolytic cavity. The Poldip2 binding inhibits the Clp function by sequestration of its necessary component. Lipoic acid-activating medium chain acyl-CoA synthetase ACSM1 is one of the Clp substrates, so Poldip2 deficiency leads to ACSM1 degradation and impaired PDC and KGDC lipoylation, which negatively affects their activity, as well as the respiration [46]. Moreover, the Poldip2 knockdown induces hypoxia-like metabolic reprogramming, regardless of the oxygen concentration. This reprogramming is manifested by enhanced glycolysis, upregulation of HIF-1α, and activation of PDKs, which phosphorylate PDH E1 and exert even deeper PDC inhibition. The HIF-1α stabilization in Poldip2-deficient cells, which leads to a pseudohypoxia state, was the most likely consequence of the impaired Krebs cycle flux due to inactive PDC and KGDC and low aKG levels. This mechanism may significantly contribute to glycolytic phenotype and OXPHOS restriction in cancer cells. Indeed, certain breast cancer cell lines (MB231, BT549) that exhibit highly glycolytic metabolism also have a very low Poldip2 protein level [46].

7.5 Regulation of pyruvate dehydrogenase complex by mitochondrial sirtuins The activity of the pyruvate dehydrogenase complex determines the fate of major energy substrates: the rate of glucose utilization, the Krebs cycle flux, and the production of reducing equivalents used in the electron transfer chain (ETC) and oxidative phosphorylation (OXPHOS), as well as provision of intermediates for lipid synthesis. Glucose utilization has far-reaching consequences for the systemic energy balance in the multicellular organism, so the PDC activity is tightly regulated by various mechanisms: by covalent modifications such as phosphorylation and acetylation; by allosteric regulation; and by lipoamide cofactor removal. The PDC phosphorylation and dephosphorylation is carried out by pyruvate dehydrogenase kinases (PDK14) and phosphatases (PDP1, and 2), respectively. The enzymatic removal of lipoamide is a recently discovered regulatory mechanism carried out by Sirt4, present both in Pro- and Eukaryota [27,28]. The other regulatory mechanism, well-studied in the case of PDC, involves serine phosphorylation of the PDH E1 subunit (S232, S293, and S300) by PDKs, which leads to inhibition of catalytic function. PDKs’ activity is also regulated either by allosteric activators (NADH, acetyl-CoA, and ATP) or by phosphorylation by signal transducing kinases. Phosphorylation of PDKs is associated with their increased activity. Various PDK isoforms (PDK14) are frequently overactive in cancer: their expression is upregulated by oncogenes (c-Myc) and by HIF-1α during hypoxia, and their activity is increased by phosphorylation, for example, phospho-Tyr 243 in PDK1, by oncogenic kinases that transduce signal from growth factor receptors [4749]. The PDK-mediated inhibition of PDC significantly contributes to the, so-called, Warburg effect and metabolic reprogramming of cancer cells toward glycolysis dependence and limited ATP generation through OXPHOS. Recent studies have pointed to the role of PDP1, which removes serine phosphorylation induced by PDKs. PDP1 is loosely associated with PDC through the interaction with the lipoyl-binding domain of E2 component in the presence of calcium ions [50]. PDP1 itself is regulated by posttranslational modifications: phosphorylation and acetylation, posing a higher-level control of PDC activity. PDP1 is phosphorylated on two tyrosine residues (Y94 and Y381) by kinases that transduce signal from growth factor receptors (e.g., epidermal and fibroblast growth factor receptors). Y94 phosphorylation inhibits PDP1 ability to bind lipoic acid and destabilizes the association with the E2 PDC component, whereas Y381 phosphorylation recruits acetyl-CoA acetyltransferase (ACAT1) to the PDP1-PDC complex with the simultaneous dissociation of Sirt3 [16]. Actually, PDP1 being a part of the PDC complex, provides a physical connection between PDC and ACAT1 and Sirt3, the two proteins that exert opposite effects on the PDC activity [16]. ACAT1 catalyzes acetylation of both PDP1 and PDH E1 components on K202 and K321, respectively. The binding of ACAT1 facilitates the recruitment of PDK1 and subsequent PDH E1 phosphorylation and inhibition. On the other hand, when PDP1 is not phosphorylated, Sirt3 is associated with the complex, keeping PDH E1 deacetylated and active. In this fashion, the PDP1 phosphorylation and acetylation status decides the overall PDC activity [16]. Multiple phosphorylation events (activating phosphorylation of PDKs, inhibiting phosphorylations of PDP1 and PDH E1) result from growth factor receptor kinases, which are frequently hyperactive in cancer cells. This growth factor-stimulated signaling serves as a trigger for the metabolic switch from oxidative pyruvate metabolism and OXPHOS (active PDC) toward intensive glycolysis and reduction of pyruvate to lactate (inactive PDC). Indeed, epidermal growth factor (EGF) signaling, for instance, stimulates glycolysis and promotes proliferation

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7.6 Alpha ketoglutarate dehydrogenase complex regulates gene expression

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FIGURE 7.2 Mitochondrial sirtuins, Sirt3, Sirt4 and Sirt5 differentially affect the enzymatic activity of several key mitochondrial dehydrogenases: pyruvate dehydrogenase complex (PDC), alpha-ketoglutarate dehydrogenase complex (KGDC), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH2). The arrows indicate positive modulation and blunt endings indicate negative impact on the enzymatic activity. Sirt4 lipoamidase activity and KGDC inhibition has been demonstrated in gram-positive and gram-negative bacteria [28], it is possible but not yet demonstrated in mammalian cells, therefore is indicated by question mark. Altered activities of these dehydrogenases lead to the imbalance of the intracellular concentrations of organic acids: succinate, fumarate, alpha-ketoglutarate (aKG). IDH1/2 mutations frequently present in particular types of cancer cells gain a neomorphic activity to form an oncometabolite 2-hydroxyglutarate. Succinate and 2-HG are inhibitors of aKG-dependent dioxygenases (TET and JmjC-domain proteins) and protein hydroxylases (PHD). Further consequences involve hypoxia-inducible factor HIF-1α stabilization, metabolic reprogramming (aerobic glycolysis, so called Warburg effect in cancer cells) and modified methylation patterns (see text).

in cancer cells [51]. In this context, Sirt3, which contributes to sustaining PDC activity, counteracts metabolic reprogramming during oncogenic transformation. Apart from deacetylation by Sirt3, PDC is also a target for Sirt5-mediated desuccinylation. A proteomic analysis revealed multiple succinylation sites on all the PDC subunits, with the highest abundance on PDH E1 [31]. PDC in embryonic fibroblasts isolated from Sirt52/2 mice was hypersuccinylated, and the treatment of purified PDC with Sirt5 resulted in desuccinylation and inhibition of the holoenzyme activity. Similarly, Sirt5 knockdown increased PDC activity as compared to control [31]. In summary, it seems that PDC is a subject of an intense activity from all three mitochondrial sirtuins, with Sirt3 exerting upregulation in contrast to Sirt4 and Sirt5 that inhibit or decrease PDC activity (Fig. 7.2). Correspondingly to the case of PDC, Sirt3 and Sirt5 exert the opposite actions on another protein crucial both for the Krebs cycle function and respiration, namely, succinate dehydrogenase (SDH). SDH is a heterotetramer consisting of two membrane-bound heme-possessing SDHC and SDHD subunits: a SDHB subunit carrying three FeS clusters and a SDHA subunit with a covalently bound FAD cofactor. SDHC and D along with the B subunit form a ubiquinone-binding site. Thirteen lysine residues of SDHA located on the protein surface can be modified by acetylation (Table 7.2). Sirt3 directly interacts with SDHA and removes this modification, which leads to increased activity of the respiratory complex II [52,53]. SDHA is also a target of succinylaton with a considerable degree of overlap with acetylation, that is, K179, 250, 335, 485, 498, 538, and 547 can be either acetylated or succinylated [31,53]. Interestingly, SDHB K276 has been identified as a succinylation, but not acetylation site. Sirt5driven desuccinylation was shown to suppress SDH activity, and concordantly, knockdown of Sirt5 induces SDH activity and overall respiration rate, as compared to the control [31].

7.6 Alpha ketoglutarate dehydrogenase complex regulates gene expression Recently, an unexpected activity of KGDC in the histone modification has been discovered in human glioma cell lines [54]. The KGDC complex mainly resides in mitochondria, but one of its components, alpha ketoglutarate dehydrogenase (KGDH), possesses a putative nuclear localization signal and a small fraction of KGDC acts in the nucleus as a binding partner for a histone acetyltransferase KAT2A. The KAT2A enzyme utilizes succinylCoA, generated by KGDC, as a substrate for histone H3 succinylation on K9. The highest enrichment in H3 succinylation was detected in the promoter regions of genes involved in cell cycle regulation or activated growth

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factor signal transduction pathways. The KAT2A knockdown significantly reduced the histone succinylation in these regions and inhibited the expression of the target genes [54]. These results point to the important epigenetic regulatory function of KGDC, apart from its metabolic roles. This context encourages us to imagine Sirt4 as a KGDC lipoamidase that could modulate gene expression patterns through this mechanism, too (Fig. 7.2).

7.7 Fluctuations of the intracellular concentration of organic acids has far-reaching implications SDH is believed to act as a tumor suppressor, and mutations in the genes coding its subunits are observed in certain hereditary malignancies, particularly of neuroectodermal origin, such as paraganglioma and pheochromocytoma [55,56]. Inactivating mutations of SDH leads to the impaired Krebs cycle flux and accumulation of succinate. Depletion of SDH in yeast cells leads to eightfold increase in succinate with a concomitant decrease in intracellular alpha-keto glutarate (aKG) to a barely detectable level [57]. Succinate is a competitive inhibitor of aKG-dependent protein hydroxylases, such as ten-eleven translocation (TET) dioxygenases, Jumonji-C domain (JmjC)-containing histone demethylases, and prolyl hydroxylases (PHDs). TET proteins and JmjC-domain histone demethylases play an important role in the epigenetic control over the expression of protooncogenes and tumor suppressor genes. TET dioxygenases (TET1, 2, 3), including aKG and ferrous ion (Fe(II))-dependent dioxygenases, are involved in removing a methylation pattern in DNA through iterative oxidations of 5-methylcytosines (mainly present in CpG dinucleotides) to 5-hydroxymethyl-, 5-formyl- and 5-carboxylcytosine [58,59]. In order to achieve a complete demethylation, the latter two cytosine derivatives are further subjected to base-excision repair mechanism by DNA glycosylases and substituted by cytosines [60,61]. DNA methylation in the gene promoter regions is usually associated with transcriptional repression and gene silencing. 5-Methyl-C (5-mC), 5-hydroxymethyl-C (5-hmC), 5-formyl-C (5-fC), and 5-carboxyl-C (5-caC) are recognized by the specialized distinct set of “reader” proteins. Methyl-CpG binding protein 2, methyl-binding domain proteins (MBPs) and Uhrf1 among others, recognize methylated cytosines, whereas another set of “chromatin readers” prefer binding to nonmethylated cytosines or 5-hmC with a very little overlap [62]. The pattern and abundance of cytosine methyl-modification is not only tissue specific (with a particularly high hmC presence in brain), but also depends on the developmental stage and is associated with the transition from pluripotency to a differentiated state [62,63]. It is not surprising then, that TET proteins dysregulation (e.g., loss of function mutations, missense mutations) and subsequent alterations in cytosine methyl- and oxidized methyl derivatives are frequently observed in cancers, such as acute myeloid leukemia (AML) [64]. JmjC-domain-containing histone demethylases (KDMs) are an important group of enzymes involved in epigenetic regulation on the level of modulation of histone methylation pattern. Recent studies revealed that a removal of some or all methyl residues from lysines (they can be mono-, di-, or tri-methylated) in histone tail regions is quite a dynamic process, important for chromatin remodeling, and activation or repression of gene transcription. The characteristic JmjC domain is a double-stranded β helix fold that coordinates Fe(II) and aKG during the catalysis. The demethylation reaction is carried out by hydroxylation of a methyl group with oxygen, aKG, Fe(II) as substrates and succinate, CO2, and Fe(III) are released as products. Ascorbate is necessary for the regenerative reduction of Fe(III) to Fe(II), during which dehydroascorbate is formed [65]. The newly formed hydroxymethyl group (i.e., hydroxymethyl hemiaminal intermediate) spontaneously decomposes to formaldehyde, leaving a demethylated lysine [66]. KDMs are subdivided into several families (KDM27) that demethylate mainly histone H3 at the K4, K9, K27, and K36 sites [67]. KDMs have been implicated in cancer both as tumor suppressors or oncogenes, depending on the cancer cell type [68]. For instance, in the case of KDM5 (JARID1) the tumor suppressive activities included improving genomic stability, cooperation with retinoblastoma protein (pRB) in pancreatic cancer, and induction of cellular senescence [69,70], whereas in breast cancer JARID1B has been revealed as an oncogene [71]. JARID1B has been also implicated in the maintenance of cancer stem cell potential in melanoma cells and support of continuous tumor growth [72]. Scarce levels of aKG lead to inhibition of prolyl hydroxylases such as EglN1. Normally, these enzymes catalyze protein hydroxylation on proline residues using aKG and oxygen as substrates and producing carbon dioxide and succinate. HIF-1α is one of the most important substrates of PHD, implicated in oncogenesis, malignant transformation, and tumor metabolic adaptation to hypoxia [47]. Hydroxylated HIF-1α is ubiquitinated by von Hippel Lindau (VHL tumor suppressor) ubiquitin ligase and subjected to proteolytic degradation [73]. HIF-1α has a very short halflife (roughly several minutes), but in the low oxygen conditions PHD are not active, HIF-1α is not hydroxylated,

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which remarkably improves its stability [74]. In case of aKG depletion this situation also takes place regardless of oxygen concentration, which leads to a pseudohypoxia state. HIF-1α is responsible for enforcing glycolysis, block of respiration, and development of an invasive, metastatic phenotype. As described above, the decreased intracellular concentration of aKG and high level of succinate may have profound consequences in the alterations of DNA and histone methylation pattern, as well as facilitate adaptation of cancer cells to hypoxia through the stabilization of HIF-1α. With an even more disturbing effect on the activity of aKG-dependent enzymes are two glutaric acid derivatives, namely D-2-hydroxyglutarate and L-2-hydroxyglutarate (2-HG), which structurally resemble closely aKG. D-2-HG is a product of particular mutants of isocitrate dehydrogenase IDH1 or IDH2 that gain neomorphic activity of aKG reduction to D-2-HG. The mutations responsible for that change affect one of the three arginine residues crucial for isocitrate binding: R132 in IDH1 or R140 and R172 in IDH2 protein and R residue is substituted with another polar amino acid, usually H, C or S [75]. These mutations are remarkably frequent (60%80%) in grade II and III astrocytomas, secondary gliomas, and AML (20%) [7678]. IDH1 (present mostly in cytoplasm and peroxisomes) and IDH2 (mitochondrial) are structurally similar and in usual conditions perform NADP-dependent oxidative decarboxylation of isocitrate to aKG. The third IDH enzyme, mitochondrial IDH3 is not related to IDH1 and 2, and is a bona fide Krebs cycle enzyme using NAD. In hypoxic conditions, the cancer cells, particularly those addicted to avid glutamine consumption, perform glutaminolysis, which is glutamine deamination to glutamate and subsequent oxidation of glutamate to aKG (anaplerosis). In these cells, IDH1 and 2 perform reductive carboxylation of aKG to isocitrate, which is further converted to citrate and exported from mitochondria to cytoplasm, where it is a substrate for fatty acid synthesis. Hypoxic conditions and low pH promote accumulation of both D- and L-2-HG, as result of mutant IDH1/2 or moonlighting activities of lactate and malate dehydrogenases (LDH, MDH) [7981]. Both D- and L-2-HG inhibit aKG-dependent enzymes in a similar fashion to succinate (see above), and indeed the hypoxia-induced L-2-HG accumulation was shown to alter the histone methylation pattern through inhibition of KDM4C [79]. Both 2-HG enantiomers can be oxidized to aKG by FAD-dependent D-2-HG and L-2-HG dehydrogenases (D2HGDH and L2HGDH, respectively). These flavoproteins are located at the inner mitochondrial membrane and transfer the electrons derived from 2-HG to FAD and later to ubiquinone in the ETC, supporting the mitochondrial membrane potential maintenance during hypoxia [80]. 2-HG aciduria and the D2HGDH and L2HGDH deficiencies have been linked to development of certain malignancies, such as diffuse large B-cell lymphoma and invasive brain tumors [82,83]. Loss of TET2 and IDH1/2 neomorphic mutations result in an overlapping genomic cytosine hypermethylation pattern in AML, which results in increased expression of stem cell markers (c-kit) and impaired myeloid differentiation [84]. These changes significantly contribute to a malignant phenotype of this type of cancer. Concluding, the perturbations in the Krebs cycle flux lead to imbalance in the concentrations of the intermediate metabolites, namely aKG, succinate, and fumarate, which exert a significant impact on the epigenetic regulation of gene transcription. Mitochondrial sirtuins, by affecting PDC, KGDC, and SDH activity, have a crucial role in the control of the Krebs cycle flux and indirectly influence the transcriptional profile (Fig. 7.2).

7.8 Ketogenic enzymes ACAT1 and HMGCS2 as substrates for Sirt3 and Sirt5 Protein acetylation by ACAT1 is quite unexpected, because this enzyme is involved in ketogenesis and produces acetoacetyl-CoA from two acetyl-CoA molecules. This novel role of ACAT1 directly links this protein with tumor progression. Fan and colleagues demonstrated that knockdown of its expression severely impairs cancer cell proliferation under hypoxia (naturally occurring in solid tumors), because it slows down glycolysis. Human lung cancer cells lacking ACAT1 grew much slower and formed significantly smaller tumors in athymic mice, showing reduced proliferative capacity [16]. Most likely, these cells had their metabolism fixed on pyruvate oxidation, which was difficult in the hypoxic tumor microenvironment, and were unable to adapt to anaerobic glucose utilization [16]. In light of these results, ACAT1 seems to contribute to the Warburg effect (intense glycolysis despite the presence of oxygen), frequently observed in transformed cells of various origins. As mentioned in Section 7.4, ACAT1 and Sirt3 affect PDC in the opposite directions through modifications of PDH E1 acetylation status. Another intriguing interaction between Sirt3 and ACAT1 in the context of regulation of the cellular response to nutritional stimuli, was reported in the liver mitochondria from fasted and refed mice [20]. A proteomic analysis showed that several proteins involved in major mitochondrial metabolic processes (Table 7.2) possess multiple sites with dynamically changing acetylation status. Among these proteins ACAT1

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was revealed to be an enzyme involved in the majority of these pathways, namely ketogenesis, fatty acid oxidation, and branched chain amino acid metabolism. Three acetylated lysin residues were identified as Sirt3 targets: K187, K260, and K265 in murine protein (K190, K263, and K268 in human protein). Acetylation at these sites (especially K260 and K265, adjacent to CoA binding site) changed the charge in the catalytic pocket and inhibited ACAT1 enzymatic activity, by affecting the basic kinetic parameters: decreasing maximal velocity (Vmax) and increasing the Michaelis constant (Km) for CoA [20]. During fasting, Sirt3 deacetylated ACAT1 enhancing its activity, which has an important role in adaptation to decreased nutrient availability. Interestingly, K265 is also succinylated and desuccinylated by Sirt5. Embryonic fibroblasts-derived Sirt52/2 mice show 120-fold increased abundance in K265 succinylation compared to the wild phenotype [31]. Sirt3 and Sirt5 have also been shown to deacylate and activate 3-hydroxy-3-methylglutaryl synthase 2 (HMGCS2), the enzyme catalyzing the rate-limiting step of ketogenesis. Both sirtuins target multiple lysine residues on HMGCS2, but K301 seems to be particularly important for the enzymatic activity [21,32,39]. In the three-dimensional structure of the protein, this residue lies in close proximity to a 30 -phosphate group of acetyl-CoA, and the acetylation or succinylation of this residue eliminates a positive charge necessary for the proper interaction with the substrate. The deacylation of HMGCS2 by Sirt3 and Sirt5 greatly induces its activity and promotes ketogenesis [21,32]. At this time Sirt3 and Sirt5 act concordantly, not oppositely, as was the case for PDC. The relation between ketone body metabolic pathway and oncogenic phenotype is puzzling, because numerous previous reports indicated that the malignant cells have difficulties in performing ketone body oxidation, which is the process that engages ACAT1 activity [85,86]. ACAT1 is involved both in ketogenesis, which is the process of ketone body (acetoacetate and 3-hydroxybutyrate) synthesis, and in ketolysis, that is, the ketone body catabolic pathway. Nevertheless, some particular cancer cells, such as melanoma cells harboring the activating mutation (V600E) in the protooncogenic kinase BRAF, have been shown to benefit from the synthesis of acetoacetate, one of the ketone bodies [87,88]. In these cells, acetoacetate-generating HMG-CoA lyase (HMGCL) expression is crucial for sustaining proliferative potential [87]. The activating point mutation of BRAF (V600E) is very frequent in melanoma, present roughly in 50% cases, and confers a highly proliferative, particularly invasive, and glycolytic phenotype [89,90].

7.9 Antagonistic roles of mitochondrial sirtuins in fed and fasted state The cooperation between Sirt3 and Sirt5 in the promotion of ketogenesis is a part of the bigger picture of these two sirtuins as the chief coordinators of the cellular response to fasting. Their expression is higher in the liver mitochondria of fasted mice, compared to the fed animals [91]. Both Sirt3 and Sirt5 are also involved in the positive regulation of fatty acid beta oxidation, by deacylation and activation of the enzymes involved in this process, such as long-chain and very-long-chain acyl-CoA dehydrogenases (LCAD, VLCAD). Other enzymes, for example, trifunctional protein (enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-ketothiolase), have also numerous Sirt3- and Sirt5-targeted lysine residues [22,39]. Particularly, Sirt3 and Sirt5 target K299 of VLCAD, which is important for FAD cofactor binding and the catalytic activity. Sirt5 desuccinylates also K482, K492, and K507, which are responsible for the interaction with cardiolipin and the inner mitochondrial membrane binding [23]. In contrast to Sirt3 and Sirt5, Sirt4 is active in the nutrient abundant conditions and inhibits fatty acid oxidation in muscle and promotes lipid anabolism in adipose tissue [30]. Malonyl-CoA (a substrate for cytosolic de novo fatty acid synthesis) inhibits carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls long fatty acyl chains’ entrance to mitochondria for beta oxidation. Malonyl-CoA decarboxylase (MCD) cleaves malonyl-CoA into CO2 and acetyl-CoA. MCD is acetylated on six lysine residues: K58, K167, K316, K388, and K444 and on evolutionary conservative K210 and K471 [30,92]. Sirt4 possesses a weak deacetylase activity specifically toward K471. MCD with K471Ac exhibits elevated enzymatic activity that promotes malonyl-CoA decomposition and intensifies fatty acid oxidation. In the fed state, Sirt4 deacetylates MCD K471, which reduces its enzymatic activity and the malonyl-CoA can enter fatty acid synthesis as a substrate. Depletion of Sirt4 in hepatocytes increases fatty acid oxidation and the Sirt4 2/2 mice present better exercise capacity and lower weight gain than wild-type littermates, when fed with a high-fat diet [30,93]. In this way, Sirt4 stimulates lipogenesis in nutrient-rich conditions and plays an opposite physiological role to Sirt3 and Sirt5.

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7.10 The interplay between Sirt3 and isocitrate dehydrogenase in cancer cells The studies performed in MEFs derived from Sirt32/2 mice directly demonstrated the role of Sirt3 as a mitochondrial tumor suppressor: maintaining the proper cellular defense against reactive oxygen species (ROS), genotoxic and metabolic stress factors, and protection of genome stability [94]. Sirt3-deficient cells exhibited a tumor permissive phenotype that facilitated immortalization and subsequent oncogenic transformation with tumorforming ability in vivo [94]. The metabolic consequences of Sirt3 loss were typical for neoplastic reprogramming, with increased glycolytic rate and decreased activity of respiratory complexes I and III, leading to overall inhibition of OXPHOS. This action of Sirt3 as a tumor suppressor is linked to maintaining redox homeostasis through maintaining the proper reduced-to-oxidized glutathione ratio (GSH/GSSG). This is carried out by deacetylation and activation of IDH2 that generates NADPH, a reducing equivalent important for glutathione reductase/thioredoxin cycling [95]. The acetylation of IDH2 K413 prevents the homodimerization of the enzyme and severely impedes its activity. Sirt3-mediated deacetylation of IDH2 restores the dimerization and increases the activity (Fig. 7.2). The cells expressing acetylation-mimetic IDH2 mutant (K413Q) show elevated intracellular ROS levels, metabolic shift toward glycolysis, and tumor-permissive phenotype [96]. The dependence of Sirt3 tumor suppressing activity on IDH2 seems unexpected, bearing in mind the high frequency of IDH1/2 mutations in glioma and AML. However, the analysis of randomized controlled trials and prospective and retrospective studies on malignant brain tumor patients indicate that these IDH1/2 R132H/R172 mutations are associated with better prognosis and higher overall survival rate [97]. Sirt3 or IDH1/2 loss create a transformation-permissive environment, but of course are only small elements of the whole picture.

7.11 Tumor-suppressing and tumor-promoting activities of sirtuins in the context of glutamine and glucose metabolism In healthy nontransformed cells, the exposure to DNA damaging agents induces DNA repair response and concomitantly, the cell cycle is arrested. Cell cycle block provides a safety mechanism meant to limit genomic instability and to prevent the increased mutation incidence in the cell progeny. The failure to block cell proliferation in the conditions of genotoxic stress leads to genomic instability, which is an intrinsic feature of oncogenic transformation and frequently observed in various cancer types. Highly proliferative cells, including cancer cells, have obviously an increased demand for deoxyribonucleotide supply to satisfy replication and DNA repair. These cells avidly consume glutamine, which fuels the Krebs cycle flux through anaplerosis. In this process, glutamine is first deaminated to glutamate by glutaminase (GLS1) and next glutamate is converted to aKG by glutamate dehydrogenase (GDH). aKG acts as a carbon supply for the Krebs cycle, and can be either oxidized to succinyl-CoA by KGDH, as happens in the nontransformed cells, or reductively carboxylated to isocitrate by the reverse reaction catalyzed by IDH2 in cancer cells, mainly during hypoxia. The glutaminolytic flux is an important metabolic signal that supports proliferation. Sirt4 has been shown to act as a metabolic tumor suppressor through the repression of glutamine-driven anaplerosis in response to genotoxic stress and DNA damage [98]. The mechanism of this action involves Sirt4-driven inhibition of both GLS1 and GDH. The latter enzyme is ADP-ribosylated by Sirt4, which negatively impacts its catalytic activity [26]. It is not entirely clear if there is a direct interaction between GLS1 and Sirt4, nevertheless GLS1 has two putative succinylation sites: K130 and K164, that might be sirtuin deacylation targets. The inhibition of glutaminolysis by Sirt4 results in decreased glutamine-derived carbon flux to the Krebs cycle, which is a blocking signal for cell cycle progression during the genotoxic stress of either irradiation or exposure to chemical DNA-damaging agents [98]. Sirt4-deficient cells exhibited much faster clonogenic growth and tumor formation in the mouse xenograft model than wild-type counterparts, which the illustrates tumor suppressive activity of Sirt4. Interestingly, recent studies by Greene and collaborators have shown that Sirt5 has a totally opposite effect on the glutamine metabolism than Sirt4. Sirt5-mediated desuccinylation of GLS1 protects it from ubiquitination and proteolytic degradation and therefore contributes to maintenance of stable high protein levels of GLS1 [34]. Sirt5 activity supports glutaminolysis, which translates into enhanced proliferation and breast cancer tumorigenesis. The study revealed also that the high Sirt5 expression level correlated with poor prognosis for the breast cancer patients [34]. Sirt5 is also overexpressed in nonsmall cell lung cancer (NSCLC) and has been linked to drug resistance and higher probability of recurrence, appearing therefore as a poor survival prognostic factor [99].

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The cancer-promoting activities of Sirt5 are not limited only to glutaminolysis. This sirtuin demalonylates and activates eight out of ten glycolytic enzymes (including GAPDH, aldolase, phosphoglucose isomerase, and pyruvate kinase) [38], therefore facilitating acquisition of glucose-addicted phenotype and the Warburg effect. A study by Xiangyun and coauthors [35] presents pyruvate kinase M2 isoenzyme (PKM2) as a direct target of Sirt5 in lung cancer cell line. PKM2 is often highly expressed in embryonic and cancer cells, because it provides a growth advantage in highly proliferative, glycolytic cells. Pyruvate kinases catalyze an irreversible step of glycolysis, which is dephosphorylation of phosphoenolpyruvate (PEP) to pyruvate with simultaneous ATP formation, therefore their activity is a major contribution to the overall glycolysis rate. PKM2 is one of the PK isoenzymes (along with hepatic PKL, PKR expressed in erythrocytes, and a constitutively active PKM1), but not a particularly active one, and frequently inhibited by posttranslational modifications, such as phosphorylation and acetylation [100]. Its expression enables the redirection of glycolytic intermediates into biosynthetic processes: the pentose phosphate pathway (PPP) and amino acid synthesis, important for the proliferating cells [100]. The PKM2 succinylation on K498 is necessary for the catalytic activity. Sirt5 physically binds and desuccinylates PKM2 leading to its inactivation. PKM2 inactivation shunts glucose catabolism almost entirely toward the PPP, which is one of the major sources of intracellular NADPH (apart from IDH1/2 activity). Sirt5 activity helps to sustain high NADPH levels and therefore provides the better protection against oxidative stress, which translates to higher proliferation rate and accelerated tumor formation in the mouse xenograft model, as compared to the cells treated with Sirt5 inhibitor, suramin [35]. In support of the evidence of a positive role of Sirt5 in tumor growth promotion, Sirt5 overexpression has been demonstrated in numerous hepatocellular carcinoma cell (HCC) lines, in comparison to normal liver cell line (LO2) [101]. Sirt5 knockdown significantly reduced proliferation rate in HCC lines and induced apoptosis, suggesting a prosurvival role of Sirt5. The authors infer that the possible mechanism of antiapoptotic action of Sirt5 involves cytochrome c deacetylation [101]. Summing up, Sirt3 and Sirt4, despite their contrasting roles in the several aspects of the cellular metabolism, for example, fatty acid oxidation, act as tumor suppressors via repression of glutamine catabolism and promotion of respiration. Sirt5 clearly stands on the opposite side, by activating the metabolic routes important for sustaining proliferation and promotion of tumor growth in vivo.

7.12 Sirtuins regulate ironsulfur cluster assemblage Sirt3 regulates iron absorption and intracellular nonheme iron content. The Sirt3-deficient cells have an inappropriate regulation of iron metabolism [102]. Normally, in sufficient intracellular iron concentration the iron regulatory proteins 1 and 2 (IRP1, IRP2) induce ferritin expression for safe iron storage and inhibit transferrin receptor 1 (TfR1) expression by a respective stabilization or degradation of their transcripts [103,104]. Sirt2/2 MEFs show upregulated expression of transferrin receptor 1 (TfR1) and iron uptake, while downregulating ferritin and ferroportin 1 expression [102]. These cells show also the symptoms of oxidative stress and higher ROS levels in comparison to wild-type controls. The exposure to ROS leads to destruction of FeS clusters and induces conversion of cytosolic aconitase to IRP1 that controls stability of transcripts of genes involved in iron metabolism [103,104]. Apart from the role in iron storage regulation, Sirt3 is responsible for cellular protection against ROS [94]. Proliferating cancer cells have an increased demand for iron as a necessary cofactor for numerous metabolic enzymes, as well as the proteins engaged in nucleic acid synthesis. Indeed, TfR1 expression is activated in c-Myc transformed cells and contributes to sustaining proliferation [105]. Sirt3 inhibits IRP1 in pancreatic cancer cells decreasing their clonogenic growth [102]. In conclusion, Sirt3 acts as a tumor suppressor by keeping a tight regulation of iron uptake and storage and Sirt3 loss provides a growth advantage for the transformed cells. Apart from the indirect impact of Sirt3 on the aconitase activity through oxidative stress management, there is also a direct interaction between these two proteins. The mass spectrometric analyses revealed that mitochondrial aconitase possesses multiple acetylation sites and their acetylation is associated with a high enzymatic activity. Sirt3 inhibits it through deacetylation and this process is implicated in the modulation of response to high fat diet [17].

7.13 Mitochondrial fatty acid synthesis is linked to FeS cluster assembly and protein lipoylation—implications for cancer cell metabolism As discussed above, Sirt3 emerged as a regulator of iron metabolism and storage, which affects FeS cluster formation. The most common FeS cluster cofactors present rhombic [2Fe2S] or cubic [4Fe4S] geometry

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(Fig. 7.3), whereas [3Fe4S] and higher order complexes, such as [8Fe7S] are less common [106]. The FeS clusters are inserted into target apoproteins by mitochondrial ISC and cytoplasmic CIA systems. The ISC machinery consists of a scaffold protein ISCU, cysteine desulfurase NFS1, desulfurase-interacting protein ISD11 (LYRM4), frataxin (FXN), and mitochondrial acyl-carrier protein (mtACP) [107109]. Mammalian CIA system includes scaffold protein NUBP1/2, IOP1 involved in the cluster transfer, CIAO1, and CIAPIN1 (Anamorsin) [110]. The ISC components FXN and mtACP are also the key players in the regulation of mitochondrial metabolism. FXN is an evolutionary conservative nuclear-encoded mitochondrial protein acting as an iron chaperone, and involved in the defense against ROS [111]. Frataxin deficiency is associated with a neurodegenerative disorder named Friedereich’s Ataxia (FRDA), multiple metabolic abnormalities, and organ dysfunction, as well as liver cancer development in the mouse model of this disease [112]. In ISC complex, FXN allosterically activates persulfide formation by NFS1, which is an essential step in FeS biogenesis [113]. Frataxin protects the aconitase FeS cluster from disassembly and stabilizes its enzymatic activity [114], therefore contributing to sustaining the Krebs cycle flux [115]. The loss of mitochondrial aconitase activity is an indicator of high superoxide production and oxidative stress [114]. Through supporting the function of respiratory complexes, FXN promotes OXPHOS and also acts as a tumor suppressor: targeted disruption of frataxin in hepatocytes induces liver tumor formation in mice [116,117]. This latter function might also be linked with FXN’s role in improving the efficiency of DNA repair mechanisms after the exposure to genotoxic agents and reduces mutation frequency [112]. In cardiomyocytes isolated from FRDA model mice, FXN dysfunction leads to an 85-fold increase in NAD/NADH ratio, as a consequence of the mitochondrial metabolic imbalance [118]. Such a large increase in NAD concentration inhibits Sirt3 and leads to mitochondrial protein hyperacetylation and respiratory defects on the cellular level, which translate into FRDA-associated cardiomyopathy on the systemic level [118,119]. mtACP is a crucial member of the ISC complex that physically interacts with Isd11 and facilitates the FeS assembly. The Isd11 (LYRM4)-NFS1-FXN complex provides Fe and S atoms to form a complete cluster at the scaffold protein ISCU. The cluster is next transferred onto a target protein by the ISCU-HSPA9-HSC20 chaperone complex [120,121]. Apart from this role, mtACP is involved in a highly conserved mitochondrial mtFAS, which is inherited from an alpha-proteobacterial mitochondrial predecessor (see Chapter 3, Sirtuins and Metabolic Regulation: Food and Supplementation). mtFAS is carried out by separate proteins: acyl-carrier protein (mtACP), malonyl-CoA:ACP transferase (MCAT), ketoacyl-ACP synthase (OXSM), 3-ketoacyl-ACP reductase (KAR1), 3-hydroxyacyl-ACP dehydratase (HTD2), and 2-enoly-ACP reductase (MECR) [10]. In contrast to the mitochondrial pathway, the cytoplasmic fatty acid synthesis (FASI) is carried out in mammalian cells by fatty acid synthase, a dimer

FIGURE 7.3 Schematic illustration of the most common types of ironsulfur (FeS) clusters with examples of proteins harboring them. ETC, Electron transfer chain; LIAS, lipoic acid synthase; RNR III, ribonucleotide reductase class III; SDHB, succinate dehydrogenase subunit B.

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formed by two large multidomain polypeptides that possesses seven enzymatic activities (starting from N-terminus, they are as follows: 3-ketoacyl synthase, acyl-S-transferase, 3-ketoacyldehydratase, enoyl reductase, 3-ketoacyl reductase, acyl carrier protein, and thioesterase). Cytoplasmic FASI produces fatty acids for triglyceride and phospholipid formation, whereas the main function of mtFAS is the synthesis of lipoic acid and several sphingolipid species. mtFAS utilizes acetyl-CoA and malonyl-CoA affecting their mitochondrial concentrations. The fluctuations of these active acyl intermediates are reflected in the protein acylation and the pathways regulated by mitochondrial sirtuins. The mtACP activity depends on the attachment of a 4-phophopantetheine (4-PP) prosthetic group to the conserved S82 residue [122]. Therefore mitochondrial phosphopantetheinyltransferase 2 (Ppt2) which moves 4-PP moiety from CoA to ACP, is an important auxiliary protein for mtFAS [123]. In mtFAS, mtACP serves as a soluble scaffold that facilitates transfer of acyl intermediates among the other enzymes involved in the pathway [122]. mtFAS is able to synthesize acyl chains of up to 14 carbon atoms in length, but octanoic acid, a lipoic acid precursor, is its most important product. The experiments on yeast cells expressing mtACP mutant S82A, which cannot be 4-phosphopantetheinylated, demonstrated that the defects in FeS biogenesis in these cells result from an inability to form acyl-ACP, and not from the lack of lipoic acid synthesis [122]. Therefore the treatment with exogenous lipoic acid does not rescue the cells with mtFAS defects [122]. mtACP is also a structural component and the accessory subunit of the respiratory complex I (NADH:ubiquinone oxidoreductase) [124,125]. To play this role, mtACP must possess the 3-hydroxymyristoyl chain bound to the 4-PP group. During the ETC complex assembly, mtACP binds to LYR (Leu-Tyr-Arg) motif proteins (LYRMs). LYRMs are small hydrophilic proteins that act as assembly factors for respiratory complexes I, II, III, and V, and take part in the FeS cluster formation [120]. mtACP deficiency destabilizes also respiratory complex II (succinate:CoQ dehydrogenase), probably due to the defects in FeS assembly and leads to inactivation of lipoamide-dependent enzymatic complexes, such as PDC and KGDC [123]. As was shown on the example of Isd11, the formation of LYRM-ACP complex requires mtACP acylation (usually 3-hydroxymyristoylation). The acyl chain is inserted into the LYRM hydrophobic pocket [10,126]. This interaction leads to the allosteric activation of LYRM proteins and supports of ETC complex biogenesis. During lipoic acid synthesis, LIAS is an important recipient of FeS clusters and mtACP provides octanoyl chain as a substrate. To insert sulfur atoms into octanoyl chain, LIAS probably uses FeS cluster from the Isd11/NFS1/mtACP complex [120]. The mtACP activity affects also mitochondrial tRNA processing [127,128]. One of mtFAS’ peculiarities is the fact that in vertebrates HTD2 and RPP14 subunits of RNAse P are encoded by the same bi-cistronic transcript, which is extremely unusual for Eukaryota. The experiments on yeast cells also revealed connections between mtFAS and RNA processing: the defects in mtFAS are associated with problems in RNAse P activity in mitochondria [128]. RNAse P performs endonucleolytic cleavage of the 50 end of tRNAs during their maturation. Additionally, mtACP is a structural component of human mitochondrial ribosomes and cooperates with LYRMs in the assembly of large ribosomal subunits [129] and therefore is indispensable for the mitochondrial translation. In summary, mtFAS controls mitochondrial metabolism by several mechanisms: (1) lipoic acid supply for PDC, KGDC etc.; (2) support of FeS cluster assembly for the Krebs cycle enzymes; (3) ETC complex assembly; and (4) RNAse P-mediated tRNA processing and mitochondrial translation (including the mitochondrially encoded ETC components) [123]. mtFAS is also a part of the general mechanism that controls the mitochondrial homeostasis by responding to the nutritional status. The control is exerted through acetyl-CoA fluctuations: acetyl-CoA is a carbon source for the Krebs cycle, but also for mtFAS, which generates both the lipoic acid and acyl chain for ACP, which is crucial for ETC complex assembly and respiration. In general, the mitochondrial acetyl-CoA level is the resultant of anabolic (citrate export for fatty acid synthesis, ketogenesis) and catabolic (input from glucose, amino acid, and fatty acid catabolism) processes. As described in previous sections, mitochondrial sirtuins control all these pathways and therefore have a crucial impact on the acetyl-CoA level. On the other hand, mitochondrial acetyl-CoA determines the rate of protein acetylation which impacts their activity. So, the balance between acetyl-CoA level and sirtuin activity serves as a nutritional sensor for maintenance of mitochondrial homeostasis.

7.14 Consequences of FeS cluster defects in cancer cells FeS cluster-containing proteins play several crucially important cellular functions (as already mentioned previously): (1) they are the components of the ETC complexes (e.g., 8 FeS centers in the complex I, 3 centers in the complex II, Rieske proteins in the complex III); (2) they belong to the Krebs cycle (aconitase, fumarase,

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FIGURE 7.4 Mitochondrial sirtuins, particularly Sirt3, affect ironsulfur (FeS) cluster assembly and maintenance by two mechanisms: (1) through supporting effective cellular mechanisms of antioxidative protection, (2) by the control of the labile iron storage and iron metabolism. FeS containing proteins (indicated by gray box arrows) play multiple and diverse roles, crucial for cellular homeostasis (indicated by smaller blue arrows). The numerous metabolic pathways that employ FeS proteins, are the source of reactive acyl thioesters (acetyl-CoA, succinyl-CoA, malonyl-CoA, etc.) that can nonenzymatically acylate cellular proteins that are sirtuin targets. ETC, Electron transfer chain.

succinate dehydrogenase); (3) they take part in lipoic acid synthesis (LIAS); (4) they control tRNA modifications (TYW1, CDKAL1, CDK5RAP1, ELP3 catalyzing tRNA nucleotide thiolation and isoprenylation); (5) they regulate iron homeostasis (IRP1/cytosolic aconitase); (6) they are required for DNA repair (MUTYH, XPD and RTEL1 helicases, FancJ, Endonuclease III, DNA glycosylases) and replication (δ-, ε-, ζ- DNA polymerases, primase); and finally (7) they take part in reduction of ribonucleotides to deoxyribonucleotides (RNRs). Mitochondrial sirtuins, particularly Sirt3 contribute to the control of labile iron pool through various mechanisms including antioxidative protection which has a direct impact on the FeS cluster assembly. Defective FeS cluster assembly, which happens in cancer cells, therefore, translates into metabolic perturbations: impaired OXPHOS and deregulation of the Krebs cycle, which may lead to succinate accumulation and has consequences in altered epigenetic regulation (Figs. 7.2 and 7.4). The consequences of FeS absence were studied in the cells expressing the conditional dominant negative ISCU C69S mutant, which are unable to ligate the nascent FeS cluster [130]. These cells exhibited dramatic alterations in the metabolism: the loss of PDC and KGDC activity (due to lipoic acid deficiency), OXPHOS blockade, and inactivation of aconitase (due to lack of FeS centers) resulted in acute citrate accumulation. The restriction in the Krebs cycle flux caused the export of citrate pool to cytoplasm and its subsequent conversion to lipids via the cytoplasmic FASI pathway and abundant lipid droplet formation [130]. A heavy lipid droplet load is very common in cancer cells, being one of the adaptations to hypoxia and oxidative stress and provides a significant growth advantage [131]. The therapeutic implications of lipid droplet accumulation are severe, because lipophilic cytotoxic anticancer drugs can be absorbed and stored in lipid droplets, and sequestered from their molecular targets, leading to drug resistance [132]. The impairment of FeS cluster machinery significantly contributes to oncogenic transformation and tumor progression (Fig. 7.4). One example of such a process involves MMS19, an adaptor protein from the cytosolic CIA system. MMS19 interacts with numerous DNA repair proteins (MUTYH, XPD, DNA glucosylases, FancJ) and helps them acquire FeS clusters necessary for the proper function [133]. MAGE-F1 modulatory protein, overexpressed in several types of cancer (including lung cancer, esophageal cancer, head and neck carcinoma), binds to MMS19 and induces its ubiquitination and degradation [133]. It is possible that induction of MAGE-F1 is a response to insufficient intracellular iron content, which also happens in cancer cells [133]. When cytosolic FeS cluster transfer is impaired the DNA repair machinery does not function properly, which in turn leads to progressive genomic instability. High mutation rate and genomic instability are cancer driving force, frequently observed for instance in breast cancer with loss of function mutations in BRCA1/2 genes [134].

7.15 Deoxyribonucleotide synthesis—toward the as yet unexplored areas of sirtuin research The actual engagement of sirtuins in the evolution of DNA via deoxyribonucleotide synthesis is still more than enigmatic. Discovery of RNR shed new light on the classical “chicken and egg” problem of the origin of DNA and the encoded proteins [135]. DNA is synthesized from deoxyribonucleotides, which are produced from

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ribonucleotides (not just by assemblage of deoxyribose and nucleobases) via reduction of carbon 20 of the ribose ring with the use of RNR [6]. The mechanism of this reaction is strictly free radical-dependent and demands sophisticated processes of initiation and then transfer of the free valency electron through the chain of aminoacyl radicals placed, for example, in the class Ia RNR in the interphase between two subunits coded in human in different chromosomes to the enzyme active site [7,8]. To achieve such a long-distance transfer of electrons highly specialized complexes of proteins revealing surface-active structural properties must be involved [8]. Consequently, DNA must have evolved in the world of highly specialized proteins encoded in RNA genomes. The problem is that nowadays RNR are divided into several surprisingly different groups varying primarily in the mechanism of initiation, and appearing in various groups of organisms: i) the already mentioned “aerobic” class I RNR (divided into Ia and Ib group), ii) the “in-between” class II RNRs present with no dependence on the oxygen demand in microorganisms, and iii) the “anaerobic” class III RNRs present in strictly anaerobic and facultatively aerobic organisms under strictly anaerobic conditions, besides other “atypical” variants of RNRs. Altogether, these enzymes occur in all the main domains of organisms [7]. The common feature of all RNRs is the ultimate appearance of the thiyl radical (RS•) being the direct donor of the electron to reduce the ribose moiety [8,136]. The actual role of mitochondrial sirtuins in this process is not known. But remembering their engagement in the intracellular iron sensing, it becomes extremely intriguing also from this point of view. Firstly, because of the cosmopolitan presence and universal engagement of both groups of enzymes in the metabolism of all major groups of organisms, and secondly, because of the role of nonheme iron in the reduction of ribonucleotides. Either in the form of diiron-oxo complexes in the RNR class I, and as [4Fe4S] clusters in RNR III [137]. There is almost no doubt, at present, that the most ancient is the RNR III class of the enzymes [7]. It appears almost exclusively under strictly anaerobic conditions even in facultative anaerobes. It is dependent on ironsulfur clusters (the [4Fe4S] type), which generate the oxygen-sensitive glycyl radical depending on formate as the electron donor, and S-adenosylmethionine and flavodoxin [7,136]. There is a convincing hypothesis that RNR I may have originated only in the world containing atmospheric dioxygen [7]. Namely, the initiating agent (thioredoxin or glutaredoxin, or nucleotide reductase “supporting” enzyme NrdH) serving to reduce the tyrosyl residue to the tyrosyl radical cooperates with the diiron-oxo class of iron complexes [138]. Here a question arises concerning the assemblage of this type of iron complex versus their evolutionary origin in the context of FeS clusters. Perhaps there was an interphase in the evolution, when the dioxygen-dependent diiron-oxo complexes were generated in trace, catalytic amounts, as the trace-like presence of oxygen in the primordial neutral or reducing atmosphere cannot be excluded [139]. There is an interplay between this form of iron and ironsulfur clusters, because diiron-oxo complexes have been detected in the system repairing FeS cluster in E. coli (RIC) [140].

7.16 Perspectives—evolutionary implications and new directions in cancer treatment Numerous metabolic disorders that result from improper functioning of mitochondria, are related to sirtuins (Sirt4) [141]. On the other hand, mitochondria are critically dependent in their functions on the support of deoxyribonucleotides, which in mammals are produced in the cytoplasm or even depend on the cytoplasmic transit of extracellular deoxyribonucleotides to mitochondria [7]. Not accidentally, the first steps of elementary, “prebiotic” evolution, as strongly depended on the supply of monomers for template-dependent replication, were heading for the process of autonomic nucleotide synthesis [142]. One must be reminded that the support of deoxyribonucleotides is important not only for DNA synthesis in the S-phase (thus proliferation of cancer cells), but also for DNA repair (in the nucleus but also in the mitochondrion [143]), so that the expression of RNR is even regulated by the absorbed doses of ionizing irradiation [144]. Consequently, it seems a good idea to develop new strategies for cancer treatment via targeting ribonucleotide reduction. And indeed, based on targeting RNR activity, however, via sirtuin-independent glutaredoxin and thioredoxin inhibition, Haffo et al. have reactivated the p53 pathway in human osteosarcoma, and caused an inhibition of cell growth [145]. There are several other concepts of RNR-targeted cancer therapies [146]. But more recently, Chen et al. have shown that Sirt2 (admittedly, a nonmitochondrial sirtuin) is really engaged in the control of RNR activity and responsible for deoxyribonucleotide support in human lung cancer cells, constituting such a potential target. Interestingly, the anticancer activity of Sirt2 is based on its deacetylase activity [147]. The further dissection of the sirtuin-RNR interdependence is therefore of crucial importance. The evolutionary aspects of these problems, leading to the better understanding of the coevolution of irontriggered and iron-sensing processes, sirtuins, and DNA synthesis/repair may, consequently, identify new

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targets for therapies, and new concepts for cancer treatment. A good example may be the actual mitochondrial localization of the interested processes. Mitochondria are believed to evolutionary originate from alphaproteobacteria, which still exist as intracellular “superparasites” depending on the cellular metabolism to the degree only slightly weaker than some viruses [148]. Rickettsias, for instance, are considered to be organisms closely related to eukaryotic protomitochondria, but they do not produce ATP, instead exchanging it for ADP with the host’s cellular sources [149]. Meanwhile, closely related intracellular pathogens, for example, Chlamydia, produce their own deoxyribonucleotides, with a modified class Ia RNR, and this modification has been proven to reveal adaptive value in the intracellular parasitism [150,151]. Moreover, the most enigmatic anaerobic RNRs were “suddenly” discovered in the genome of bacteriophage T4 [152], where the presence of a type I RNR gene was itself found as an astonishing phenomenon in the late 1960s [153]. Clearly, a focus on sirtuin functioning in Rickettsias, Chlamydias, or DNA-phages, still poorly understood, should contribute to the better exploration of mitochondrial sirtuin-related targets for therapeutic purposes. Little is known about the interactions between sirtuins and RNRs, and every newly discovered fact brings new applicative ideas. There is, for example, the problem of the actual origin of sirtuins, which, as transferases, may be rooted in the elementary processes of biogenesis as deeply as RNRs. As there is no “evolutionary vacuum,” many executors of biological functions in the present biological systems possessed other roles in the past. For protoribosomes, for instance, it may have been just template-dependent synthesis of RNA [154,155]. The idea of evolutionary horror vacui demands to name the primary function of sirtuins, as well as of RNRs, as in the preDNA world it must have NOT been reduction of ribonucleotides, unless to satisfy the demand for DNA synthesis. This is, obviously, a clearly unexplored field in the development of new anticancer strategies, and the same for understanding the neoplastic transformation itself. In the light of the above-described phenomena the cancer cell is a cell revealing genetic disorders which, speaking in a common mode, not only “move it backward in the ontogenesis (to gain a more embryonic phenotype),” but also in phylogeny (to take advantage of more primitive metabolic pathways and regulations). The mitochondrial sirtuins (Sirt3) strongly affect the iron metabolism, in particular, control of nonheme iron turnover, serving as a support for “the iron sensor,” the already mentioned, but inactive cytosol aconitase serving as IRP-1 [114,156]. The action of this system is dependent on Sirt3 (in Sirt32/2 mice the assemblage of FeS clusters is impaired, see Section 7.12). The main active form of sulfur in the process of FeS cluster formation is the persulfide anion RSS2, itself quite easily oxidizable to perthiyl radical (RSS•) which, contrary to the thiyl radical, is stabilized by resonance, thus responding for the electron transfer properties of persulfide [157,158]. This is a very ancient trace of biogenesis. Generation of [4Fe4S] clusters in the most ancient RNR class III makes it able to generate the reaction-active thiyl radical (common for all RNRs), which in class I RNR (typical for humans) is a consequence of the activity of the dioxygen-dependent diiron-oxo complex [7]. The appearance of thiyl radical even for the most ancient RNR is therefore preceded by the perthiyl radical/persulfide anion. The question is whether this order of events reflects the actual phylogenetic order of events? The possibility to enzymatically generate FeS clusters must be at least as old, or even older than the enzymatic generation of the [4F4S] complexes in the most ancient RNR III [159]. It is difficult to answer whether already on that stage of biogenesis the system of iron-sensing triggered by Sirt 3 and defective IRP1 was active. But in this light it is iron and sulfur that should be really considered as the bona fide “biogenic” elements setting the whole carbon-scaffolded machinery of life in evolutionary motion.

References [1] Zachar I, Szilagyi A, Szamado S, Szathmary E. Farming the mitochondrial ancestor as a model of endosymbiotic establishment by natural selection. Proc Natl Acad Sci U S A 2018;115(7):E150410. [2] Pittis AA, Gabaldon T. Late acquisition of mitochondria by a host with chimaeric prokaryotic ancestry. Nature 2016;531(7592):1014. [3] Martin WF, Roettger M, Ku C, Garg SG, Nelson-Sathi S, Landan G. Late mitochondrial origin is an artifact. Genome Biol Evol 2017;9 (2):3739. [4] Tanaka N, Kanazawa M, Tonosaki K, Yokoyama N, Kuzuyama T, Takahashi Y. Novel features of the ISC machinery revealed by characterization of Escherichia coli mutants that survive without ironsulfur clusters. Mol Microbiol 2016;99(5):83548. [5] Tsaousis AD. On the origin of iron/sulfur cluster biosynthesis in eukaryotes. Front Microbiol 2019;10:2478. [6] Jordan A, Reichard P. Ribonucleotide reductases. Annu Rev Biochem 1998;67:7198. [7] Nordlund P, Reichard P. Ribonucleotide reductases. Annu Rev Biochem 2006;75:681706. [8] Chang MC, Yee CS, Stubbe J, Nocera DG. Turning on ribonucleotide reductase by light-initiated amino acid radical generation. Proc Natl Acad Sci U S A 2004;101(18):68827. [9] Fuss JO, Tsai CL, Ishida JP, Tainer JA. Emerging critical roles of Fe-S clusters in DNA replication and repair. Biochim Biophys Acta 2015;1853(6):125371.

I. Sirtuins and metabolic disease

122

7. Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation

[10] Masud AJ, Kastaniotis AJ, Rahman MT, Autio KJ, Hiltunen JK. Mitochondrial acyl carrier protein (ACP) at the interface of metabolic state sensing and mitochondrial function. Biochim Biophys Acta Mol Cell Res 2019;1866(12):118540. [11] Greiss S, Gartner A. Sirtuin/Sir2 phylogeny, evolutionary considerations and structural conservation. Mol Cell 2009;28(5):40715. [12] Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J, et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 2006;23(4):60718. [13] Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009;325(5942):83440. [14] Verdin E, Ott M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat Rev Mol Cell Biol 2015;16(4):25864. [15] Wagner GR, Payne RM. Widespread and enzyme-independent Nepsilon-acetylation and Nepsilon-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J Biol Chem 2013;288(40):2903645. [16] Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014;53(4):53448. [17] Fernandes J, Weddle A, Kinter CS, Humphries KM, Mather T, Szweda LI, et al. Lysine acetylation activates mitochondrial aconitase in the heart. Biochemistry 2015;54(25):400818. [18] Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A 2006;103(27):102249. [19] Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell 2013;51(4):50618. [20] Still AJ, Floyd BJ, Hebert AS, Bingman CA, Carson JJ, Gunderson DR, et al. Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regulation. J Biol Chem 2013;288(36):2620919. [21] Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 2010;12(6):65461. [22] Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010;464(7285):1215. [23] Zhang Y, Bharathi SS, Rardin MJ, Uppala R, Verdin E, Gibson BW, et al. SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA dehydrogenase. PLoS One 2015;10(3):e0122297. [24] Hallows WC, Yu W, Smith BC, Devries MK, Ellinger JJ, Someya S, et al. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 2011;41(2):13949. [25] Bao X, Wang Y, Li X, Li XM, Liu Z, Yang T, et al. Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach. eLife 2014;3:118. [26] Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006;126(5):94154. [27] Mathias RA, Greco TM, Oberstein A, Budayeva HG, Chakrabarti R, Rowland EA, et al. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 2014;159(7):161525. [28] Rowland EA, Snowden CK, Cristea IM. Protein lipoylation: an evolutionarily conserved metabolic regulator of health and disease. Curr Opin Chem Biol 2018;42:7685. [29] Anderson KA, Huynh FK, Fisher-Wellman K, Stuart JD, Peterson BS, Douros JD, et al. SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab 2017;25(4):83855 e15. [30] Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 2013;50(5):68698. [31] Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 2013;50(6):91930. [32] Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 2013;18(6):92033. [33] Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 2011;334(6057):8069. [34] Greene KS, Lukey MJ, Wang X, Blank B, Druso JE, Lin MJ, et al. SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis. Proc Natl Acad Sci U S A 2019;116(52):2662532. [35] Xiangyun Y, Xiaomin N, Linping G, Yunhua X, Ziming L, Yongfeng Y, et al. Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth. Oncotarget 2017;8(4):698493. [36] Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 2014;19(4):60517. [37] Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteom 2011;10(12) M111 012658. [38] Nishida Y, Rardin MJ, Carrico C, He W, Sahu AK, Gut P, et al. SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol Cell 2015;59(2):32132. [39] Rardin MJ, Newman JC, Held JM, Cusack MP, Sorensen DJ, Li B, et al. Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. Proc Natl Acad Sci U S A 2013;110(16):66016. [40] UniProt. UniProt database ,https://www.uniprot.org.; 2020 (accessed 04.06.2020). [41] Zhang Y, Bharathi SS, Rardin MJ, Lu J, Maringer KV, Sims-Lucas S, et al. Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain. J Biol Chem 2017;292(24):1023949. [42] Carrico C, Meyer JG, He W, Gibson BW, Verdin E. The mitochondrial acylome emerges: proteomics, regulation by sirtuins, and metabolic and disease implications. Cell Metab 2018;27(3):497512.

I. Sirtuins and metabolic disease

References

123

[43] Landgraf BJ, McCarthy EL, Booker SJ. Radical S-adenosylmethionine enzymes in human health and disease. Annu Rev Biochem 2016;85:485514. [44] Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab 2017;25(1):2742. [45] Solmonson A, DeBerardinis RJ. Lipoic acid metabolism and mitochondrial redox regulation. J Biol Chem 2018;293(20):752230. [46] Paredes F, Sheldon K, Lassegue B, Williams HC, Faidley EA, Benavides GA, et al. Poldip2 is an oxygen-sensitive protein that controls PDH and alphaKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer. Proc Natl Acad Sci U S A 2018;115(8):178994. [47] Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006;3(3):17785. [48] Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006;3(3):18797. [49] Hitosugi T, Fan J, Chung TW, Lythgoe K, Wang X, Xie J, et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell 2011;44(6):86477. [50] Maj MC, Cameron JM, Robinson BH. Pyruvate dehydrogenase phosphatase deficiency: orphan disease or an under-diagnosed condition? Mol Cell Endocrinol 2006;249(12):19. [51] Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 2008;13(6):47282. [52] Cimen H, Han MJ, Yang Y, Tong Q, Koc H, Koc EC. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 2010;49(2):30411. [53] Finley LW, Haas W, Desquiret-Dumas V, Wallace DC, Procaccio V, Gygi SP, et al. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS One 2011;6(8):e23295. [54] Wang Y, Guo YR, Liu K, Yin Z, Liu R, Xia Y, et al. KAT2A coupled with the alpha-KGDH complex acts as a histone H3 succinyltransferase. Nature 2017;552(7684):2737. [55] Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287(5454):84851. [56] Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69(1):4954. [57] Smith EH, Janknecht R, Maher 3rd LJ. Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma. Hum Mol Genet 2007;16(24):313648. [58] Parker MJ, Weigele PR, Saleh L. Insights into the biochemistry, evolution, and biotechnological applications of the ten-eleven translocation (TET) enzymes. Biochemistry 2019;58(6):45067. [59] Scourzic L, Mouly E, Bernard OA. TET proteins and the control of cytosine demethylation in cancer. Genome Med 2015;7(1):9. [60] He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 2011;333(6047):13037. [61] Dong C, Zhang H, Xu C, Arrowsmith CH, Min J. Structure and function of dioxygenases in histone demethylation and DNA/RNA demethylation. IUCrJ 2014;1(Pt 6):5409. [62] Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PW, Bauer C, et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 2013;152(5):114659. [63] Globisch D, Munzel M, Muller M, Michalakis S, Wagner M, Koch S, et al. Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS One 2010;5(12):e15367. [64] Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114(1):1447. [65] Young JI, Zuchner S, Wang G. Regulation of the epigenome by vitamin C. Annu Rev Nutr 2015;35:54564. [66] Accari SL, Fisher PR. Emerging roles of JmjC domain-containing proteins. Int Rev Cell Mol Biol 2015;319:165220. [67] Verrier L, Vandromme M, Trouche D. Histone demethylases in chromatin cross-talks. Biol Cell 2011;103(8):381401. [68] Chang S, Yim S, Park H. The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Exp Mol Med 2019;51(6):117. [69] Chicas A, Kapoor A, Wang X, Aksoy O, Evertts AG, Zhang MQ, et al. H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. Proc Natl Acad Sci U S A 2012;109(23):89716. [70] Lin W, Watanabe H, Peng S, Francis JM, Kaplan N, Pedamallu CS, et al. Dynamic epigenetic regulation by menin during pancreatic islet tumor formation. Mol Cancer Res 2015;13(4):68998. [71] Yamamoto S, Wu Z, Russnes HG, Takagi S, Peluffo G, Vaske C, et al. JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 2014;25(6):76277. [72] Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A, et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 2010;141(4):58394. [73] del Peso L, Castellanos MC, Temes E, Martin-Puig S, Cuevas Y, Olmos G, et al. The von Hippel Lindau/hypoxia-inducible factor (HIF) pathway regulates the transcription of the HIF-proline hydroxylase genes in response to low oxygen. J Biol Chem 2003;278(49):486905. [74] Ternette N, Yang M, Laroyia M, Kitagawa M, O’Flaherty L, Wolhulter K, et al. Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency. Cell Rep 2013;3(3):689700. [75] Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360 (8):76573. [76] Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 2008;116(6):597602. [77] Deng L, Xiong P, Luo Y, Bu X, Qian S, Zhong W, et al. Association between IDH1/2 mutations and brain glioma grade. Oncol Lett 2018;16(4):54059.

I. Sirtuins and metabolic disease

124

7. Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation

[78] DiNardo CD, Ravandi F, Agresta S, Konopleva M, Takahashi K, Kadia T, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol 2015;90(8):7326. [79] Intlekofer AM, Dematteo RG, Venneti S, Finley LW, Lu C, Judkins AR, et al. Hypoxia Induces Production of L-2-Hydroxyglutarate. Cell Metab 2015;22(2):30411. [80] Nadtochiy SM, Wang YT, Zhang J, Nehrke K, Schafer X, Welle K, et al. Potential mechanisms linking SIRT activity and hypoxic 2-hydroxyglutarate generation: no role for direct enzyme (de)acetylation. Biochem J 2017;474(16):282939. [81] Oldham WM, Clish CB, Yang Y, Loscalzo J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab 2015;22(2):291303. [82] Lin AP, Abbas S, Kim SW, Ortega M, Bouamar H, Escobedo Y, et al. D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nat Commun 2015;6:7768. [83] Haliloglu G, Jobard F, Oguz KK, Anlar B, Akalan N, Coskun T, et al. L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings. Neuropediatrics 2008;39(2):11922. [84] Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010;18(6):55367. [85] Maurer GD, Brucker DP, Bahr O, Harter PN, Hattingen E, Walenta S, et al. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer 2011;11:315. [86] Tisdale MJ, Brennan RA. Metabolic substrate utilization by a tumour cell line which induces cachexia in vivo. Br J Cancer 1986;54 (4):6016. [87] Kang HB, Fan J, Lin R, Elf S, Ji Q, Zhao L, et al. Metabolic rewiring by oncogenic BRAF V600E links ketogenesis pathway to BRAFMEK1 signaling. Mol Cell 2015;59(3):34558. [88] Grabacka M, Plonka PM, Reiss K. Melanoma-time to fast or time to feast? An interplay between PPARs, metabolism and immunity. Exp Dermatol 2020;29(4):43645. [89] Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol 2018;31(1):2438. [90] Lu H, Liu S, Zhang G, Kwong LN, Zhu Y, Miller JP, et al. Oncogenic BRAF-mediated melanoma cell invasion. Cell Rep 2016;15 (9):201224. [91] Li L, Zhang P, Bao Z, Wang T, Liu S, Huang F. PGC-1alpha promotes ureagenesis in mouse periportal hepatocytes through SIRT3 and SIRT5 in response to glucagon. Sci Rep 2016;6:24156. [92] Nam HW, Lee GY, Kim YS. Mass spectrometric identification of K210 essential for rat malonyl-CoA decarboxylase catalysis. J Proteome Res 2006;5(6):1398406. [93] Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 2010;285(42):319952002. [94] Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010;17(1):4152. [95] Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A 2008;105(38):1444752. [96] Zou X, Zhu Y, Park SH, Liu G, O’Brien J, Jiang H, et al. SIRT3-mediated dimerization of IDH2 directs cancer cell metabolism and tumor growth. Cancer Res 2017;77(15):39909. [97] Chen JR, Yao Y, Xu HZ, Qin ZY. Isocitrate dehydrogenase (IDH)1/2 mutations as prognostic markers in patients with glioblastomas. Medicine (Baltim) 2016;95(9):e2583. [98] Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013;23(4):45063. [99] Lu W, Zuo Y, Feng Y, Zhang M. SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer. Tumour Biol 2014;35(11):10699705. [100] Dayton TL, Jacks T, Vander Heiden MG. PKM2, cancer metabolism, and the road ahead. EMBO Rep 2016;17(12):172130. [101] Zhang R, Wang C, Tian Y, Yao Y, Mao J, Wang H, et al. SIRT5 promotes hepatocellular carcinoma progression by regulating mitochondrial apoptosis. J Cancer 2019;10(16):387182. [102] Jeong SM, Lee J, Finley LW, Schmidt PJ, Fleming MD, Haigis MC. SIRT3 regulates cellular iron metabolism and cancer growth by repressing iron regulatory protein 1. Oncogene 2015;34(16):211524. [103] Hentze MW, Kuhn LC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci U S A 1996;93(16):817582. [104] Hanson ES, Leibold EA. Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species. Gene Expr 1999;7 (46):36776. [105] O’Donnell KA, Yu D, Zeller KI, Kim JW, Racke F, Thomas-Tikhonenko A, et al. Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol Cell Biol 2006;26(6):237386. [106] Ohki Y, Imada M, Murata A, Sunada Y, Ohta S, Honda M, et al. Synthesis, structures, and electronic properties of [8Fe-7S] cluster complexes modeling the nitrogenase P-cluster. J Am Chem Soc 2009;131(36):1316878. [107] Lill R, Hoffmann B, Molik S, Pierik AJ, Rietzschel N, Stehling O, et al. The role of mitochondria in cellular ironsulfur protein biogenesis and iron metabolism. Biochim Biophys Acta 2012;1823(9):1491508. [108] Wiedemann N, Urzica E, Guiard B, Muller H, Lohaus C, Meyer HE, et al. Essential role of Isd11 in mitochondrial ironsulfur cluster synthesis on Isu scaffold proteins. EMBO J 2006;25(1):18495. [109] Fox NG, Yu X, Feng X, Bailey HJ, Martelli A, Nabhan JF, et al. Structure of the human frataxin-bound ironsulfur cluster assembly complex provides insight into its activation mechanism. Nat Commun 2019;10(1):2210. [110] Sharma AK, Pallesen LJ, Spang RJ, Walden WE. Cytosolic ironsulfur cluster assembly (CIA) system: factors, mechanism, and relevance to cellular iron regulation. J Biol Chem 2010;285(35):2674551.

I. Sirtuins and metabolic disease

References

125

[111] Shoichet SA, Baumer AT, Stamenkovic D, Sauer H, Pfeiffer AF, Kahn CR, et al. Frataxin promotes antioxidant defense in a thioldependent manner resulting in diminished malignant transformation in vitro. Hum Mol Genet 2002;11(7):81521. [112] Thierbach R, Drewes G, Fusser M, Voigt A, Kuhlow D, Blume U, et al. The Friedreich’s ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals. Biochem J 2010;432(1):16572. [113] Patra S, Barondeau DP. Mechanism of activation of the human cysteine desulfurase complex by frataxin. Proc Natl Acad Sci U S A 2019;116(39):1942130. [114] Bulteau AL, Ikeda-Saito M, Szweda LI. Redox-dependent modulation of aconitase activity in intact mitochondria. Biochemistry 2003;42 (50):1484655. [115] Martelli A, Puccio H. Dysregulation of cellular iron metabolism in Friedreich ataxia: from primary ironsulfur cluster deficit to mitochondrial iron accumulation. Front Pharmacol 2014;5:130. [116] Schulz TJ, Thierbach R, Voigt A, Drewes G, Mietzner B, Steinberg P, et al. Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. J Biol Chem 2006;281(2):97781. [117] Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A 1999;96(20):114925. [118] Wagner GR, Pride PM, Babbey CM, Payne RM. Friedreich’s ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase. Hum Mol Genet 2012;21(12):268897. [119] Stram AR, Wagner GR, Fogler BD, Pride PM, Hirschey MD, Payne RM. Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich’s ataxia cardiomyopathy. PLoS One 2017;12(5):e0178354. [120] Angerer H. Eukaryotic LYR proteins interact with mitochondrial protein complexes. Biology (Basel) 2015;4(1):13350. [121] Maio N, Rouault TA. Ironsulfur cluster biogenesis in mammalian cells: new insights into the molecular mechanisms of cluster delivery. Biochim Biophys Acta 2015;1853(6):1493512. [122] Van Vranken JG, Jeong MY, Wei P, Chen YC, Gygi SP, Winge DR, et al. The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis. eLife 2016;5:111. [123] Nowinski SM, Van Vranken JG, Dove KK, Rutter J. Impact of mitochondrial fatty acid synthesis on mitochondrial biogenesis. Curr Biol 2018;28(20):R121219. [124] Sackmann U, Zensen R, Rohlen D, Jahnke U, Weiss H. The acyl-carrier protein in Neurospora crassa mitochondria is a subunit of NADH:ubiquinone reductase (complex I). Eur J Biochem 1991;200(2):4639. [125] Angerer H, Radermacher M, Mankowska M, Steger M, Zwicker K, Heide H, et al. The LYR protein subunit NB4M/NDUFA6 of mitochondrial complex I anchors an acyl carrier protein and is essential for catalytic activity. Proc Natl Acad Sci U S A 2014;111 (14):520712. [126] Van Vranken JG, Nowinski SM, Clowers KJ, Jeong MY, Ouyang Y, Berg JA, et al. ACP acylation is an acetyl-CoA-dependent modification required for electron transport chain assembly. Mol Cell 2018;71(4):56780 e4. [127] Clay HB, Parl AK, Mitchell SL, Singh L, Bell LN, Murdock DG. Altering the mitochondrial fatty acid synthesis (mtFASII) pathway modulates cellular metabolic states and bioactive lipid profiles as revealed by metabolomic profiling. PLoS One 2016;11(3):e0151171. [128] Hiltunen JK, Schonauer MS, Autio KJ, Mittelmeier TM, Kastaniotis AJ, Dieckmann CL. Mitochondrial fatty acid synthesis type II: more than just fatty acids. J Biol Chem 2009;284(14):901115. [129] Li X, Sun Q, Jiang C, Yang K, Hung LW, Zhang J, et al. Structure of ribosomal silencing factor bound to Mycobacterium tuberculosis ribosome. Structure 2015;23(10):185865. [130] Crooks DR, Maio N, Lane AN, Jarnik M, Higashi RM, Haller RG, et al. Acute loss of ironsulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells. J Biol Chem 2018;293(21):8297311. [131] Bensaad K, Favaro E, Lewis CA, Peck B, Lord S, Collins JM, et al. Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep 2014;9(1):34965. [132] Rak S, De Zan T, Stefulj J, Kosovic M, Gamulin O, Osmak M. FTIR spectroscopy reveals lipid droplets in drug resistant laryngeal carcinoma cells through detection of increased ester vibrational bands intensity. Analyst 2014;139(13):340715. [133] Weon JL, Yang SW, Potts PR. Cytosolic ironsulfur assembly is evolutionarily tuned by a cancer-amplified ubiquitin ligase. Mol Cell 2018;69(1):11325 e6. [134] Zamborszky J, Szikriszt B, Gervai JZ, Pipek O, Poti A, Krzystanek M, et al. Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions. Oncogene 2017;36(6):74655. [135] Reichard P, Baldesten A, Rutberg L. Formation of deoxycytidine phosphates from cytidine phosphates in extracts from Escherichia coli. J Biol Chem 1961;236:11507. [136] Torrents E, Sahlin M, Sjo¨berg BM. The ribonucleotide reductase family—genetics and genomics. In: Kristoffer Andersson K, editor. Ribonucleotide reductase. New York: Nova Biomedical Books, Nova Sci Publ Inc; 2008. p. 1777. [137] Kristoffer Andersson K. General short overview of RNR and introduction. Ribonucleotide reductase. New York: Nova Biomedical Books, Nova Sci Publ Inc; 2008. p. 115. [138] Kurtz Jr. D. Structural similarity and functional diversity in diiron-oxo proteins. J Biol Inorg Chem 1997;2:15967. [139] Slesak I, Kula M, Slesak H, Miszalski Z, Strzalka K. How to define obligatory anaerobiosis? An evolutionary view on the antioxidant response system and the early stages of the evolution of life on Earth. Free Radic Biol Med 2019;140:6173. [140] Nobre LS, Garcia-Serres R, Todorovic S, Hildebrandt P, Teixeira M, Latour JM, et al. Escherichia coli RIC is able to donate iron to ironsulfur clusters. PLoS One 2014;9(4):e95222. [141] Betsinger CN, Cristea IM. Mitochondrial function, metabolic regulation, and human disease viewed through the prism of Sirtuin 4 (SIRT4) functions. J Proteome Res 2019;18(5):192938. [142] Eigen M. Selforganization of matter and the evolution of biological macromolecules. Naturwissenschaften 1971;58(10):465523. [143] Thelander L. Ribonucleotide reductase and mitochondrial DNA synthesis. Nat Genet 2007;39(6):7034. [144] Pulatova MK, Sharygin VL, Todorov IN. The activation of ribonucleotide reductase in animal organs as the cellular response against the treatment with DNA-damaging factors and the influence of radioprotectors on this effect. Biochim Biophys Acta 1999;1453(3):3219.

I. Sirtuins and metabolic disease

126

7. Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation

[145] Haffo L, Lu J, Bykov VJN, Martin SS, Ren X, Coppo L, et al. Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246. Sci Rep 2018;8(1):12671. [146] Aye Y, Li M, Long MJ, Weiss RS. Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies. Oncogene 2015;34(16):201121. [147] Chen G, Luo Y, Warncke K, Sun Y, Yu DS, Fu H, et al. Acetylation regulates ribonucleotide reductase activity and cancer cell growth. Nat Commun 2019;10(1):3213. [148] Kurland CG, Andersson SG. Origin and evolution of the mitochondrial proteome. Microbiol Mol Biol Rev 2000;64(4):786820. [149] Sassera D, Lo N, Epis S, D’Auria G, Montagna M, Comandatore F, et al. Phylogenomic evidence for the presence of a flagellum and cbb (3) oxidase in the free-living mitochondrial ancestor. Mol Biol Evol 2011;28(12):328596. [150] Bollinger Jr. JM, Jiang W, Green MT, Krebs C. The manganese(IV)/iron(III) cofactor of Chlamydia trachomatis ribonucleotide reductase: structure, assembly, radical initiation, and evolution. Curr Opin Struct Biol 2008;18(6):6507. [151] Hogbom M, Stenmark P, Voevodskaya N, McClarty G, Graslund A, Nordlund P. The radical site in chlamydial ribonucleotide reductase defines a new R2 subclass. Science 2004;305(5681):2458. [152] Young P, Ohman M, Sjoberg BM. Bacteriophage T4 gene 55.9 encodes an activity required for anaerobic ribonucleotide reduction. J Biol Chem 1994;269(45):2781518. [153] Berglund O, Karlstrom O, Reichard P. A new ribonucleotide reductase system after infection with phage T4. Proc Natl Acad Sci U S A 1969;62(3):82935. [154] Jeffares DC, Poole AM, Penny D. Relics from the RNA world. J Mol Evol 1998;46(1):1836. [155] Poole AM, Jeffares DC, Penny D. The path from the RNA world. J Mol Evol 1998;46(1):117. [156] Lushchak OV, Piroddi M, Galli F, Lushchak VI. Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species. Redox Rep 2014;19(1):815. [157] Benchoam D, Cuevasanta E, Moller MN, Alvarez B. Persulfides, at the crossroads between hydrogen sulfide and thiols. Essays Biochem 2020;64(1):15568. [158] Everett SA, Wardman P. Perthiols as antioxidants: radical-scavenging and prooxidative mechanisms. Methods Enzymol 1995;251:5569. [159] Ollagnier S, Mulliez E, Gaillard J, Eliasson R, Fontecave M, Reichard P. The anaerobic Escherichia coli ribonucleotide reductase. Subunit structure and iron sulfur center. J Biol Chem 1996;271(16):941016.

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C H A P T E R

8 Sirtuins and the hallmarks of cancer Talita H.B. Gomig, Tayana S. Jucoski, Erika P. Zambalde, Alexandre L.K. Azevedo, Daniela F. Gradia and Enilze M.S.F. Ribeiro Genetics Postgraduation Program, Genetics Department, Federal University of Parana´, Curitiba, Brazil O U T L I N E 8.1 Introduction

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8.8 Sirtuins in reprogramming energy metabolism

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8.9 Sirtuins and cancer therapy

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8.4 Sirtuins in tumor-promoting inflammation and immune system function 136

8.10 Concluding remarks

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8.5 Sirtuins in angiogenesis

137

References

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8.6 Sirtuins in invasion and metastasis

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8.1 Introduction Cancer is a major cause of morbidity and mortality worldwide. GLOBOCAN, based on 2018 data, reports 18.1 million new cases and 9 million deaths by cancer, projecting 29.5 million new cases in 2040, making it clear that cancer is a public health problem for all countries [1]. This increase in incidence results not only by the global increase of life expectancy, but also from the current lifestyle that leads to cancer development [2]. The high numbers justify the continuing basic research on cancer to reveal the mechanisms of initiation and progression as well as new approaches of prevention and treatment. Cancer is a generic name given to a group of over 100 diseases, since each organ in the body can develop different types of cancer. In common, these diseases have an uncontrolled growth of cells and the ability to invade neighboring and distant tissues and organs, characterizing the metastasis. The process is multistep and complex, and the basis is genome instability which generates genetic changes [3]. The role of sirtuins is expanding each year in several age-related diseases, including cancer [4,5]. Sirtuins have been described in several sites of cancer. Considering their roles as a master regulator of many cellular and physiologic functions, they have effects pro- and antitumor and previous studies have shown that the sirtuins family (SIRT17) plays a role in tumorigenesis, promoting or inhibiting tumor formation [69]. The dual roles of sirtuins in malignant phenotype development are exemplified in Table 8.1. In an attempt to organize all capabilities acquired during the multistep process of a tumor, Hanahan and Weinberg [139] proposed six hallmarks of cancer as a “distinctive and complementary capabilities that enable tumor growth and metastatic dissemination.” These hallmarks are (1) sustaining proliferative signaling; (2) evading growth suppressors; (3) activating invasion and metastasis; (4) enabling replicative immortality; (5) inducing

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TABLE 8.1 Sirtuins dual role in cancer process. Biological Sirtuin process SIRT1

SIRT2

SIRT3

SIRT4

Regulation by sirtuins As cancer promoter

As cancer suppressor

Cancer type

Tumor growth

SFRP-1 [10], SFRP-2 [10], E-cadherin [10], GATA4-GATA5 [10], MLH1 [10], P53 [11], MMP2 [12], FOXO3A [12], E2F1 [13], FXR [14], H3K4 [14], H3K9 [14], HIF1ɑ [15]a, HIF2ɑ [15]a, eNOS [16], NOTCH1 [16]

ERɑ [17,18], PTEN1 [19], NF-κB [20], CYCLIN D1 [20], β-Catenin [21], STAT3 [22], BCA3-NEDD8 [23], P65 [24], FOXM1 [25], PCAF [26], BIRC5 [27], MYC [28]

Adenocarcinoma [25,28], breast [1012,17,18,23,27], Colon [10,15], Colorectal [21], Gastric [20,22], Liver [14,15], Lung [13,16,24], Osteocarcinoma [13,26], Osteosarcoma [25], Prostate [19,21,23]

Invasion and metastasis

MMP-2 [12], FOXO3A [12], BIRC5 STAT3 [22], SMAD4 [33,34] [29], AKT [30], HIFɑ [31], PGC-1ɑ [32]

Adenocarcinoma [31], breast [12,29,30,33], fibrocarcinoma [31], gastric [22], hepatocellular [31,32], kidney fibrosis [33], ovarian [29], oral [34], squamous cell [31]

Genome alterations

P53 [11], E2F1 [13], RB [35], H3K4AC [36], H4K16 [36], H3K9 [36]

KU70 [37], XPA [38], NBS1 [39], WRN [40]

Adenocarcinoma [38,39], breast [11,36], bone osteossarcoma [37], lung [13,38], osteocarcinoma [13], osteosarcoma [40], retinoblastoma [35]

Metabolism

FXR [14], H3K4 [14], H3K9 [14], ETHE1 [41], LKB1 [42], LXR [43], SREBP-1C [44]



Colorectal [41], hepatocellular [42], liver [14,43,44]

Drug resistance

XRCC1 [45], FOXO1 [46], CREB [47]



Breast [46], gastric [47], lung [45]

Angiogenesis stimulation

MMP2 [12], FOXO3A [12], eNOS [16],  NOTCH 1 [16]

Breast [12], lung [16]

Tumor growth

P73 [48], AKT1 [49], G6PD [50], PGAM [51], LDH-A [52], P53 [53], ɑtubulin [54]

ACLY [55], HIF1ɑ [56], FOXO1 [57]

Adenocarcinoma [56], colon [57], glioblastoma [48], leukemia [50], liver [54], lung [51,53,55], myeloid leukemia [49], pancreatic [52]

Invasion and metastasis

LDH-A [52], PEPCK1 [58], AKT [59]



Gastric [58], hepatocellular [59], pancreatic [52]

Genome alterations



E-Cadherin [60], CDC20 [60], H4K16 [61], PR [61], Set7 [61], CDK9 [62]

Adenocarcinoma [62], breast [60], osteossarcoma [62], papiloma [61]

Metabolism



ACLY [55], PKM2 [63]

Breast [63], lung [55]

Angiogenesis stimulation

STAT3 [64]



Colorectal [64]

Tumor growth

GDH [65], PYCR1 [66], LADH [67], NMNAT2 [68], KU70 [69], ACC1 [70]

AceCS2 [71], JNK2 [71], NOTCH1 [72], MDM2 [73], OGG1 [74], PDHA1 [75,76], PDP1 [75], HIF1ɑ [76], PDK1 [76], TFAM [77]

Breast [66], cholangiocarcinoma [76], clear cell renal [65], cervical [70], colorectal [71], gastric [67,72], glioblastoma [74], glioma [69], hepatocellular [73], lung [66,75], nonsmall cell lung cancer [68], osteosarcoma [66,71], renal cell adenocarcinoma [77]

Invasion and metastasis

SKP2 [78], ACC1 [70]

SRC [79], FAK [79]

Breast [78], cervical [70]

Genome alterations



OGG1 [74], FOXO3A [80]

Colon [80], glioblastoma [74]

Metabolism

LADH [67], ACC1 [70], SHMT2 [81], SOD2 [81]

PDHA1 [75], PDP1 [75], TFAM [77], HIF1ɑ [82], CYPD [83]

Breast [82,83], colorectal [81], cervical [70], gastric [67], lung [75], ovarian [81], renal cell adenocarcinoma [77]

Tumor growth

IDE [84]

GDH [8588], Fis-1 [89], ECADHERIN [90], ERK [91],

Breast [84], burkitt lymphoma [87], colorectal [90], esophageal squamous (Continued)

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8.1 Introduction

TABLE 8.1 (Continued) Biological Sirtuin process

SIRT5

SIRT6

SIRT7

Regulation by sirtuins As cancer promoter

As cancer suppressor

Cancer type

CYCLIN-D [91], CYCLIN-E [91], AMPKɑ [92], SIRT1 [93]

cell [86], gastric [91], glioma [85], hepatocellular [92], lung [84], neuroblastoma [93], nonsmall cell lung [89], thyroid [88]

Invasion and metastasis



GDH [86,88], FIS1 [89], E-Cadherin [90], SIRT1 [93]

Colorectal [90], esophageal squamous cell [86], neuroblastoma [93], nonsmall cell lung [89], thyroid [88], neuroblastoma [93]

Genome alterations



GDH [94], SIRT1 [93]

Adenocarcinoma [94], lung [94], neuroblastoma [93]

Metabolism



E-Cadherin [90], GDH [87,94], SIRT1 [93], ANT2 [95]a

Adenocarcinoma [94], Burkitt lymphoma [87], colorectal [90], kidney [95], lung [94], neuroblastoma [93]

Drug resistance



IL-6 [96]

Breast cancer [96]

Tumor growth

Cyt-C [97], SOD1 [98], BIRC2 [99], GLUD1 [100], E2F1 [101], LDBH [102], PKM2 [103], GLS [104]

SHMT2 [105], SDHA [106]

Breast [104], colon [105], colorectal [100], E2F1 [101], LDBH [102], PKM2 [102,103], clear cell renal cell [106], hepatocellular [97,101], lung [98,103], nonsmall cell lung [99], osteosarcoma [105]

Invasion and metastasis

E2F1 [101]



Hepatocellular [101]

Genome alterations



ACOX1 [107]

Liver [107]

Metabolism

GLS [104]



Breast cancer [104]

Drug resistance

BIRC2 [99]



Nonsmall cell lung [99]

Tumor growth

H3K9 [108], H3K9Ac [109], H3K56Ac [109], BAX [109], AMPK [110]

MYC [111], HIF1ɑ [112], VEGF [112], H3K9Ac [113], H3K56Ac [109,113], LIN28B [113], NF-κB [114], H3K9ac [115], TWIST1 [116], ERK1/2 [117], NOTCH3 [118], PKM2 [119]

Adenocarcinoma [108], erythroleukemia [111], fibrossarcoma [108], glioma [115], hepatocellular [109,117,119], lung [112], nasopharyngeal [114], nonsmall cell lung [116], ovarian [118], pancreatic [113], skin [110]

Invasion and metastasis

Ca 1 Levels [120], H3K9 [120], NUDT9 [120]

PKM2 [119]

hepatocellular [119], pancreatic [120]

Metabolism

TGFB [121], H2O2 [121], HOCL [121]

MYC [111]

erythroleukemia [111], hepatocellular [121]

Drug resistance

FOXO3 [122]



liver [122]

Angiogenesis stimulation

Ca21 levels [120], H3K9 [120], NUDT9 [120]

HIF1ɑ [112], VEGF [112]

pancreatic [120]

Tumor growth

MAPK [123], H3K18Ac [124], P53 [125], miR-34a [126], H3K18ac [126], % [127], MTOR [128], NF-κB [127], P65 GTF3C3 [128], CDC4 [129], SMAD4 [130], P38 [131], MAPK [131], DBC1 [132], ERK [133], STAT3 [133]

DDB1 [134], ELK4 [135], H3K18Ac [135]

adenocarcinoma [128,134], breast [131], colon [123], gastric [126], glioma [133], glioblastoma [124], hepatocellular [125,135], ovarian [127], osteosarcoma [129], thyroid [132] (Continued)

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8. Sirtuins and the hallmarks of cancer

TABLE 8.1 (Continued) Biological Sirtuin process

Regulation by sirtuins As cancer promoter

As cancer suppressor

Cancer type

Invasion and metastasis

MAPK [123], NF-κB [127], P65 [127], CDC4 [129], SMAD4 [130], DBC1 [132], ERK [133], STAT3 [133], Ecadherin [136]

TGFB [137], BTRCP1 [137], SMAD4 [138]

breast [137], colon [123], glioma [133], ovarian [127], osteosarcoma [129], oral squamous cell [138], prostate [130,136], thyroid [132]

Genome alterations

H3K18Ac [124]

DDX21 [138]

breast [138], glioblastoma [124]

a

Role is controversial.

angiogenesis, and (6) resisting cell death. Ten years later, the same authors [140] revisited the hallmarks and added new ones: (7) avoiding immune destruction; (8) tumor-promoting inflammation; (9) genome instability and mutation; and (10) deregulating cellular energetics. Considering the role of sirtuins in the majority of the mechanisms involved in cancer, in this chapter we will discuss some of their specific roles as hallmarks of cancer, in an attempt to demonstrate their potential as markers in diagnosis, prognosis, and therapeutics in cancer (Fig. 8.1).

8.2 Sirtuins in sustaining proliferative signaling and evading growth suppressors Cancer development and progression involves complex and interconnected signaling that sustains chronic proliferation and evades antigrowth signaling and cell death programs. Cancer cells can support proliferative signaling independently of growth factors through the constitutive activation of pathways that impact cell proliferation and fate [140,141]. Moreover, excessive proliferative signaling can also be sustained by disruption of negative-feedback mechanisms that generally operate to attenuate proliferative signaling [140]. Sirtuin functions impact some of the major aberrant signaling pathways in cancer, such as Wnt/β-catenin [142,143], PI3K/AKT/mTOR [30,143145], NF-κB [6,146], and MAPK [147]. Sirtuins are functionally related to β-catenin, the main effector in the canonical Wnt signaling pathway [143]. Interestingly, both Wnt signaling and SIRT1 orchestrate many of the same biological processes [148], and other downstream effectors of the Wnt pathway are impacted by sirtuin expression and/or activity. For example, the disheveled proteins that act as crucial messengers for several Wnt ligands are regulated by SIRT1, which may explain the diverse responses of Wnt signaling in different cellular contexts [142]. Sirtuins play dual roles in the PI3K/AKT/mTOR signaling pathway. For example, SIRT1 directly interacts with AKT promoting SIRT2 activity [30]. SIRT2 is required for optimal AKT activation and SIRT2 overexpression enhances AKT signaling and its downstream targets [149]. SIRT6 and SIRT7 negatively regulate AKT signaling at the chromatin level and through a protein complex that impairs AKT function, respectively [145,150]. Furthermore, SIRT3 overexpression can suppress the phosphorylation of AKT which impacts on the PI3K/AKT/mTOR signaling pathway [151]. SIRT-mediated regulation of mTOR has been described in response to nutrients and cellular stresses. The SIRT1 expression is induced by calorie restriction and affected by IGF signaling [144]. SIRT1 levels can negatively regulate the mTOR pathway [152]. In addition, the activation of mTORC1 (a mTOR complex) stimulates glutamine metabolism through the dehydrogenase GDH and promotes cell proliferation by repressing SIRT4, which inhibits GDH and suppresses bioenergetics and tumor proliferation [153]. Sirtuin activity impacts some of the most critical regulatory pathways involving cancer drivers, such as Ras oncoprotein, PTEN phosphatase, and mTOR kinase. SIRT1 binds to the promoters of Ras [154] and also binds, deacetylates, and activates K-Ras, a member of the Ras family most frequently mutated in cancer [155], which activates a wide range of signaling pathways, such as PI3K and RAF/MEK/ERK (members of the MAPK pathway) [147]. The regulation of Ras-ERK1/2 and the AKT pathway may be modulated by SIRT7 impacting H3K18 expression, which is essential to cell viability, migration, and cell cycle progression [156]. In contrast, another member of the Ras family, R-Ras2, can be defatty-acylated by SIRT6, which attenuates its functions in the PI3K pathway and inhibits growth of cancer cells [157].

II. Sirtuins and cancer

8.2 Sirtuins in sustaining proliferative signaling and evading growth suppressors

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FIGURE 8.1 Sirtuins as hallmarks of cancer. Pathways and molecules regulated by sirtuins in cancer development.

PTEN is a critical regulator of proliferation, survival, and cell growth that functions by antagonizing signaling through the PI3K/AKT/mTOR pathway [84]. Unregulated cell proliferation occurs in the absence of functional PTEN due to activation of a signaling cascade downstream of the AKT pathway and inhibition of the FOXO transcription factors family of tumor suppressors, which are direct substrates of AKT [158]. Several cellular stresses, such as nutritional starvation, can induce SIRT4 expression, which interacts with and reduces the stability of PTEN. Low PTEN levels inhibit the mTOR pathway and promote cell survival by accelerating autophagy to increase cell survival in a hostile environment [84]. SIRT6 also has been shown to modulate the PTEN/AKT pathway by regulating AKT and its downstream genes, MTOR, CCND1, and MYC via PTEN, which impacts on tumor progression [159]. In addition, SIRT1 promotes tumorigenesis via the PTEN/PI3K/ AKT signaling pathway [160].

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Multiple sirtuins modulate MYC activity, one of the most highly amplified oncogenes in various tumor types [161], and whose activation antagonizes Ras-induced senescence and is critical for cellular immortalization [162]. SIRT1 plays an essential role in MYC-driven tumorigenesis through feedback loops. The overexpression of MYC leads to increased SIRT1 expression, which in turn deacetylates and downregulates MYC and its target genes (i.e., telomerase reverse transcriptase, TERT) and suppresses cell growth and transformation [28]. Moreover, the MYC-mediated increase in SIRT1 protein levels also involves sequestering the SIRT1 inhibitor DBC1 which controls SIRT1 proteasomal degradation and increasing amounts of NAD1 via MYC-induced NAMPT (a NAD1 biosynthetic enzyme) expression [163]. These data suggest a MYC-NAMPT-DBC1-SIRT1 positive feedback loop that allows enhanced proliferation and survival of cancer cells. This feedback loop exemplifies SIRT1’s dual role in tumorigenesis as dependent on the stage of cell transformation [28]. In contrast, SIRT2 negatively regulates MYC and can effectively suppress cancer cell proliferation, since SIRT2 inhibition leads to MYC ubiquitination and degradation [161]. Upregulation of SIRT3 can also lead to MYC degradation [151]. Importantly, MYC target gene promoters are enriched for SIRT6, which deacetylates its H3K56 residues, inhibiting MYC transcriptional output and suppressing genes involved in ribosomal biogenesis (members of RPL protein family) and glutamine metabolism [111,164]. In fact, one of the most important functions of MYC in cancer is regulating the metabolism of the nonessential amino acid glutamine, which is primarily utilized by cancer cells and for macromolecular synthesis [164]. Low levels of SIRT6 result in an increased transcriptional output of MYC, and consequent accelerated cell proliferation, increased expression of the apoptosis inhibitor surviving, and impaired p53 and p73 apoptotic functions [111]. Furthermore, to sustain growth-stimulatory signals, cancer cells must circumvent antigrowth signaling programs, which greatly depend on tumor suppressor activities. Evasion of growth control mechanisms allows unchecked cell proliferation and prevents apoptosis, cell cycle arrest, and senescence by tumor suppressors [158]. Tumor cells may evade tumor suppressors by epigenetic mechanisms, which implicates sirtuin deacetylation activity in disrupting upstream and downstream targets of antigrowth signaling pathways. Tumor suppressor genes can stop or decelerate tumorigenesis, and Rb, p53, PTEN, Hippo, and Notch pathways are among the most important tumor suppressor genes in cancer [158]. Sirtuins play complex and important roles in regulating tumorigenesis and cancer progression by disrupting these antigrowth signals. Rb and p53 are typical tumor suppressors and gatekeepers of the cell cycle and play a role in determining cell fate: cellular proliferation, senescence, or apoptotic programs [158]. Multiple signals from intra- and extracellular sources are integrated by Rb protein and drive cell cycle progression, controlling S-phase entry when Rb is hypophosphorylated [35,158]. Rb acetylation operates as an additional regulatory mechanism, and SIRT1 has been described as a potent deacetylase for Rb. Thus active Rb is hypophosphorylated and acetylated, and SIRT1-mediated deacetylation deactivates Rb [35]. Interestingly, SIRT1 may deacetylate Rb and p53 at a common lysine motif [35]. Antigrowth functions of the p53 family involve SIRTs activities. p53 is the most widely known substrate of SIRT1, and its deacetylation by SIRT1 negatively regulates p53-mediated transcriptional activity, promoting cellular senescence in response to DNA damage [165]. p53 can also be deacetylated in the cytoplasm by SIRT2 [166], and SIRT2 inhibition leads to p53 accumulation inducing p53 canonical target genes (i.e., CDKN1A, PUMA, and NOXA) [53]. Furthermore, SIRT3 can partially abrogate p53 function, and SIRT3 overexpression upregulates p53 and its downstream factor p21 [167]. SIRT6 expression is directly activated by p53, leading to FOXO1 deacetylation and nuclear exclusion, and loss of FOXO1-induced gluconeogenesis [168]. Hippo and Notch signaling are also critically important in tumor development [140,158]. Interestingly, the Hippo pathway influences the output of multiple signaling pathways that regulate the hallmarks of cancer [140]. Activated Hippo protein has an antigrowth function by inhibiting the complex formed by YAP protein and its transcriptional coactivator TAZ [158]. YAP functions are also regulated by SIRT1-mediated deacetylation, which leads to increased cell proliferation [169]. Further, MST1, a key component of the Hippo pathway, can upregulate SIRT1 protein levels and, in contrast, also promote p53 function via SIRT1 phosphorylation, inhibiting the SIRT1-p53 interaction and SIRT1 deacetylation activity [170]. An important role of histone deacetylation by SIRT1 occurs in the Notch pathway. Transcription of the NOTCH target genes can be controlled by sirtuins by modulating histone modifications associated with gene repression, which involves SIRT1 activity [171]. SIRT3 and SIRT6 have also been shown to inhibit the expression of NOTCH1 and NOTCH3, respectively, and in both cases, this NOTCH inhibition impairs cancer cell proliferation [72,118]. In sum, sirtuins impact the main proliferative and antigrowth signaling pathways, and their dual roles in tumorigenesis can impair several growth control mechanisms, supporting excessive proliferation through many cancer drivers.

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8.3 Sirtuins and resisting cell death During tumor development, it is essential that cancer cells evolve strategies to limit or circumvent programmed cell death by apoptosis, a natural barrier to cancer progression. Autophagy is another mechanism utilized in tumor development to sustain cell survival in a stressed tumor environment. Apoptosis occurs by two major mechanisms: extrinsic and intrinsic pathways, and involves an activation cascade of cysteine proteases called caspases and regulatory proteins of the Bcl-2 family (proapoptotic: Bax, Bak, Bid, Bim/Bad, Noxa, and Puma; and antiapoptotic: Bcl-2, Bcl-W, Bcl-XL, Mcl-1, and A1) [140,172]. The sirtuin proteins can interact with additional signaling pathways and cancer drivers that regulate apoptosis, including JNK kinase, hypoxia-related HIF-1α, p53, the FOXO transcription factors, the signal transducer STAT3, and reactive oxygen species (ROS) [173,174]. In this context, SIRTs may promote prosurvival functions or, in contrast, may facilitate cell death. SIRT1 negatively regulates p53, inhibiting p53-dependent apoptosis under DNA-damage stresses and promoting DNA repair and cell survival [6]. The p53 activity can also be suppressed through MYC-induced SIRT1 expression, which decreases the transcription of proapoptotic genes and MYC-related apoptosis [162]. SIRT1 plays a role in TNF-α-induced apoptosis [24], by deacetylating NF-κB and attenuating its transcriptional activity, thus increasing apoptosis in response to TNFɑ [6]. SIRT2 and SIRT6 have also been described in deacetylation and consequently suppression of p53 and NF-κB signaling [6,175,176]. Moreover, SIRT1 and SIRT6 regulate survivin, an essential inhibitor of the apoptosis machinery [6,177]. The expression of FOXO target genes, such as Bim, is increased by deacetylation of FOXOs by sirtuins [178]. For example, SIRT1 deacetylates FOXO1, repressing its proapoptotic activity [6]. The proapoptotic FOXO3a, a downstream target of AKT, is a substrate of multiple sirtuins, including SIRT1 [179], SIRT2 [178], and SIRT5 [180]. Another member of the FOXO superfamily, the transcription factor FOXOM1, is involved in apoptosis via the SIRT7/mTOR/IGF2 pathway [181]. SIRT3 extensively participates in the regulation of apoptosis. SIRT3 regulates the levels of proapoptotic and antiapoptotic proteins (Bax/Bcl-2 ratio), mediates apoptosis involving Bcl-2 and the JNK pathway (a MAPK subfamily that promotes the expression of downstream pathways of c-Jun, p53 and p21 [182]), exerts a prosurvival role via p53 deacetylation [183], and, like SIRT1, SIRT3 can inhibit mitochondrial apoptosis by deacetylating Ku70, which prevents Bax translocation to the mitochondria [144,184,185] and induces Ku70-dependent DNA repair [184]. SIRT3 also promotes tumorigenesis through resistance to anoikis, an apoptotic cell death mechanism triggered by the loss of extracellular matrix (ECM) contacts [186]. SIRT3 overexpression sustains cell survival by reducing the ROS levels, which are thought to activate antiapoptotic proteins [187]. Under nutrient restriction, SIRT3 and SIRT4 exert antiapoptotic activity with NAMPT, protecting cells from cell death programs [188]. Furthermore, SIRT4 plays a role in apoptosis through downregulation of the apoptosis-related proteins Bax, NOX1, and p38 [189], and plays a protective role in hypoxia-induced apoptosis [190]. SIRT5 expression levels can impact proapoptotic and antiapoptotic pathways [97]. SIRT5 has been shown to deacetylate cytochrome c (Cyt c), inhibiting mitochondrial apoptosis [97,191]. Interestingly, SIRT5’s impact on apoptosis is localization-dependent: mitochondrial SIRT5 stimulates cell death, while nuclear or cytosolic SIRT5 supports cell survival [180]. SIRT6-related apoptosis can be induced through the inhibition of JAK2/STAT3 signaling [192], and modulation of the PTEN/AKT and ERK1/2 pathways [159,193]. SIRT6 overexpression drives apoptosis in cancer cells through p53 or p73 [176]. In contrast, high levels of SIRT6 upregulate Bcl-2 expression and phosphorylated-ERK, and downregulate cleaved-CASP3 and Bax, consequently increasing proliferation via the ERK1/2 pathway and suppressing apoptosis [193]. SIRT7 promotes proliferation of tumor cells through ERK and STAT3 signaling, and SIRT7 depletion suppresses ERK and STAT3 activities. which triggers apoptosis [133]. In fact, SIRT7 knockdown results in upregulation of proapoptotic proteins (cleaved-CASP3, cleaved PARP, Bax, and Bim) and downregulation of antiapoptotic proteins (Bcl-2 and Mcl-1) [126]. SIRT7 also regulates apoptosis through deacetylation and deactivation of ATM, a central kinase in the response to DNA damage whose persistent activation induces cell death [194]. In addition, SIRT7 can affect apoptosis induced by endoplasmic reticulum (ER) stress by repressing certain MYC functions [195] and can also play a role in NF-κB-mediated apoptosis [196]. Like apoptosis, autophagy is an important physiological cell response that mediates both tumor cell survival and death, and is strongly induced in cellular stress conditions and produces nutrients for cell survival during starvation. Autophagy is frequently linked to cancer initiation and progression through many autophagy-related (ATG) proteins [197] and apoptosis-interconnected programs based on regulatory circuits involving p53, PI3K, AKT, and mTOR kinases, as well as MAPK, ERK1/2, and FOXOs, which interact with multiple sirtuins.

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SIRT1 levels increase under calorie restriction in a FOXO3a-p53-nutrient sensitive manner [144,198]. p53 deacetylation by SIRT1 impacts on p53-induced apoptosis, induces autophagy, and moreover, SIRT1 deacetylates essential components of autophagy machinery, such as ATG5, ATG7, and LC3 (ATG8), stimulating autophagy [199]. In fact, SIRT1 is known to control the expression of ATG-related genes [197,200]. SIRT1 can also stimulate autophagy via FOXO1 deacetylation and Rab7 upregulation [200]. In contrast, SIRT1 inhibition can also lead to autophagy [197]. SIRT2 can inhibit autophagy under basal conditions by forming a complex with and deacetylating FOXO1, which is highly acetylated in response to oxidative stress or starvation and interacts with ATG7 to enhance autophagic cell death [199]. In addition, SIRT2 regulates mitophagy, a selective type of autophagy that removes damaged mitochondria, as well as mitochondrial function, and its protein deacetylation [201]. SIRT3 can also act as a positive regulator of mitophagy via the hypoxia pathway [199,202]. In contrast, SIRT5 depletion has been reported to promote mitochondrial fragmentation and degradation during autophagy [203]. SIRT4 can accelerate autophagy promoting cancer cell survival via downregulation of PTEN and inhibition of the mTOR pathway [84], which is also inhibited by SIRT1 and SIRT6 activities, which positively regulates cell autophagy [204]. SIRT5 has been associated with glutamine metabolism and ammonia-induced autophagy and mitophagy [205]. Interestingly, a potential crosstalk between SIRT5 in regulating SIRT3 and SIRT1 activities in autophagy has been described in cancer [206]. SIRT3 and SIRT5 positively modulate autophagy and exert a proproliferative function under certain stress conditions, while SIRT1 can affect autophagy both positively and negatively [206]. SIRT6 is a known autophagy regulator involved in cancer development in several ways, and its expression is correlated with autophagy biomarkers, such as LC3 and p62. The effects of SIRT6 on autophagy can also involve the IGF/AKT pathway, highlighting a crucial role of the SIRT6/AKT/autophagy axis in tumorigenesis [207]. SIRT7 in turn modulates autophagy to regulate TGF-β signaling via maintenance of TGF-β receptor levels [208]. Furthermore, SIRT7 may regulate tumor cell proliferation and autophagy via androgen receptor (AR) signaling and interactions with coregulators, such as SMAD4 [130]. In sum, sirtuins play essential roles in resisting cell death through their activities in cancer-related apoptosis and autophagy.

8.4 Sirtuins in tumor-promoting inflammation and immune system function Tumor progression is supported by different cell types that constitute the microenvironment. Inflammation modulates this microenvironment through bioactive molecules such as growth factors, ECM-modifying proteins, and proangiogenic factors, which function as hallmark pathways of cancer progression. Several SIRTs, such as SIRT1, SIRT3, and SIRT6, are involved in inflammation [209,210]. SIRT1 and SIRT6 interact with NF-κB, a transcription factor involved in inflammation and immune cell proliferation [24,211]. SIRT1 deacetylates K310 of the RelA/p65 subunit of NF-κB operating as a negative regulator. SIRT6 interacts with p65 and deacetylates H3K9 in target gene promoters, reducing the accessibility of NF-κB and attenuating downstream signaling pathways. SIRT6 reduction increases NF-κB transcriptional activity, which stimulates the production of inflammatory cytokines such as IL-1B, matrix metalloproteinases (MMPs), and adhesion molecules [212]. High expression of both SIRT1 and SIRT6 observed in cancer cells reduces inflammation and immune response [108]. Furthermore, SIRT1 controls proinflammatory cytokine production in immune cells through deacetylation of key transcriptional factors or, indirectly, via metabolic pathways playing an important role in immune response regulation [213,214]. SIRT1-NF-κB interactions suppress the macrophage proinflammatory phenotype that plays a role in the tumor microenvironment. In contrast, SIRT1 silencing increases activation of the c-Jun pathway by proinflammatory stimuli [215]. c-Jun interacts with c-Fos to form the AP-1 transcriptional factor, an essential molecule of tumor cell proliferation, that positively regulates c-Jun expression and prolongs AP-1 activity independent of extracellular signals. In this immune scenario, SIRT1 interacts with transcription factors and reduces T cell activation, thus SIRT1 is responsible for the immune response against the tumor. In CD41 T cells, SIRT1 reduces FOXP3 activity contributing to the more inflammatory immunological phenotype [216]. SIRT1 overexpression in macrophages reduces prostaglandin E2 production and leads to increased phagocytic percentage and tumoricidal activities of peritoneal macrophages. Low levels of SIRT1 are prejudicial to the antitumor activities of macrophages [217,218].

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SIRT3 and SIRT4 have tumor-suppressive activity in B cell malignancies. High expression of SIRT4 can inhibit the growth of Burkitt lymphoma cells, and SIRT1 and SIRT2 inhibition can increase apoptotic activity and ROS production in B-cell chronic lymphocytic leukemia (CLL) [87,219]. SIRT3 also positively regulates gene expression of antioxidant molecules that reduce ROS, and consequently inflammation [220]. The reduction of SIRT3 contributes to the increase of ROS in the tumor microenvironment and angiogenesis [82,221]. Tumor initiation involves angiogenic insufficiencies and creates hypoxic areas with high ROS concentrations favoring tumor expansion. ROS produced by hypoxia promotes the activation of HIF1α, a transcriptional factor that controls invasion and metastasis, through inactivation of its inhibitor and increasing the VEGF growth factors and their receptors (VEGFRs) that are crucial in angiogenesis [222]. In this context, sirtuins can regulate ROS production and detoxification [223] through HIF1α deacetylation. There is a lack of consensus as to whether hypoxia increases or decreases SIRT1 levels in tumor cells [224,225]. SIRT1 action on HIF1α can vary depending upon the tissue or organ. SIRT3 control of HIF stability regulates ROS levels as well as other metabolic pathways. At reduced ROS levels, SIRT3 stabilizes the HIF-degrading enzyme PHD, thus lowering HIF1α levels [82,226]. Low SIRT3 expression is observed in several tumors and cancer cell lines [82]. In hypoxia adaptation, VEGFs, VEGFRs, MMPs, adhesion molecules, PDGF, and chemokines are essential to angiogenesis, invasion, and migration, and all of these can be epigenetically regulated by sirtuins. In the tumor microenvironment sirtuins seem to interact and modulate immune system compounds to favor tumorigenesis rather than prevent it.

8.5 Sirtuins in angiogenesis Angiogenesis is the formation of new blood vessels from preexisting ones and is essential to cancer progression because it supplies oxygen and nutrients to the tumor. The ability to induce and sustain angiogenesis during tumor development occurs via an “angiogenic switch.” Different tumor cells use distinct molecular strategies to activate angiogenesis. SIRT1 deacetylates FOXO1, which is a negative regulator of angiogenesis. Effects of SIRT1 in FOXO1 activity remain controversial, with some data suggesting that deacetylation increases FOXO activity, and other data showing the opposite effect, consequently reducing or promoting angiogenesis, respectively [227,228]. SIRT1 action on FOXO family function may vary depending on the cell type and specific FOXO target genes. SIRT1 reduction in endothelial cells reduces blood vessel formation due to lowered MMP14 expression [229]. SIRT1 can also deacetylate the NOTCH intracellular domain, modulate endothelial nitric oxide synthase (eNOS) synthesis via enhanced nitric oxide (NO) production, and deacetylate AKT K19 and K20 which permit interaction with PIP3 and AKT pathway activation in endothelial cells during tumor angiogenesis [230233]. SIRT1, SIRT3, and SIRT7 are all capable of deacetylating and inactivating p53, which acts as antiangiogenic factor [82,183,234]. SIRT2 interacts with β-catenin and alters MMP expression during angiogenesis. Depletion of SIRT2 prevents STAT3 phosphorylation, reducing the VEGF transcription [64,235]. SIRT3 in turn increases endothelial cell survival in hypoxic conditions via increased deacetylation of FOXO3 [236]. In breast cancer, loss of SIRT3 increases transcription of HIF1α-induced target genes, such as VEGF, that can be produced and secreted by cancer cells to sustain endothelial cell proliferation. However, low expression of SIRT2 reduces angiogenesis, thus acting as negative regulation of cancer progression [221]. VEGF produced and secreted by cancer cells drives endothelial cell proliferation contributing to new blood vessel development. SIRT4, SIRT5, and SIRT6 make ADP-ribosylation of PARP, which regulates VEGF and VEGFR2 [237239]. Further, SIRT6 can modulate intracellular Ca21 levels and promote expression of IL-8, TNFα, and proangiogenic factors [120]. SIRT7 inhibits HIF1α and regulates downstream gene expression, such as VEGFA [240]. In some cancer metastases, SIRT7 activates the TGF-β pathway [137]. In the angiogenesis process, sirtuins play an essential role in regulating genes that control blood vessel development, providing nutrients, and oxygen to the tumor.

8.6 Sirtuins in invasion and metastasis During tumorigenesis, cells can escape the primary tumor, acquire an invasive phenotype, and travel to distant sites to metastasize. In most cancer patients, mortality is correlated with the metastatic events [241].

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Successful tumor cell invasion and migration depends on epithelialmesenchymal transition (EMT). EMT alters the cell state, through loss of cell-to-cell and celltoextracellular matrix adhesion, loss of basement membrane adhesion, and the capacity of tumor cells to evade the immune system [140]. Sirtuins play different roles in EMT depending on the cellular context, tissue of origin, and microenvironment architecture. Positive regulation of EMT can occur by TGF-β pathway activation which increases SIRT1 expression. Interaction between SIRT7, SIRT1, Zeb1, and the Twi deacetylation of the st-MBD1 complex represses the transcription of epithelial genes (i.e., E-cadherin) by H3K18 which causes promoter silencing and increases mesenchymal gene expression (i.e., N-cadherin and vimentin) [136]. Additionally, fibronectin and γ-catenin are substrates of SIRT1 during the EMT process in cancer cell lines [242]. High and low SIRT1 levels correlate with increased angiogenesis in several tumor types [243248]. Negative regulation of EMT by sirtuins involves deacetylation of SMAD3, SMAD4, and SMAD7 by SIRT1, which reduces MMP7, MMP9, and E-cadherin, inhibiting the TGF-β pathway. In metastasis, SIRT1 regulates MMP7 by deacetylating the K37 of SMAD4, which results in repression of TGF-β signaling [34]. SIRT3 negatively regulates cancer-associated fibroblasts (CAFs), known EMT inductors, where suppressed Wnt/β-catenin signaling causes EMT-associated processes. SIRT3 can also interact with FOXO3A and Twist, controlling EMT, invasion, and migration [249251]. SIRT2 induces EMT via Akt/GSK/β-catenin activation and the RAS/ERK/JNK/MMP9 pathway [58,59]. SIRT2 overexpression leads to an increase in Slug protein, which will result in the repression of transcriptional targets, like cellular adhesion molecules, and E-cadherin, associated with invasiveness and an aggressive phenotype [252]. In contrast, SIRT4 suppresses EMT by restricting mitochondrial glutamine metabolism [87,90,253]. Additionally, SIRT4 inhibits invasion and migration by blocking MAPK/ERK/MEK activity through upregulation of E-cadherin expression [89,90]. SIRT5 contributes to invasion by interacting with the transcription factor E2F1, inducing vimentin acetylation, and positively regulating SNAIL, an essential transcription factor to repress E-cadherin expression [101,254]. SIRT6 overexpression enhances ERK1/2 phosphorylation and activates MMP9, which promotes invasion and migration [255]. The deletion of SIRT6 by modulating Lin28b also contributes to metastasis [113]. Through multiple mechanisms, sirtuins can regulate expression of target genes that promote invasion and metastasis, an essential hallmark of cancer progression.

8.7 Sirtuins in genome instability and replicative immortality Tumor growth and cancer progression are often triggered by DNA mutations, including those in genes that regulate DNA repair pathways and, subsequently, affect genomic stability [256]. DNA damage response (DDR) mechanisms, including base-excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR), and nonhomologous end-joining (NHEJ), are activated both from external agents, like UV radiation, and by molecules of cellular metabolism, like ROS [257]. During genotoxic stress, which sets foci for DDR-related proteins by recruiting DNA damage factors [258261] SIRT1 promotes HR by deacetylating WRN (a RecQ DNA helicase) [262,263]. In the NHEJ pathway, SIRT1 enhances DNA repair through Ku70 and KAP1 deacetylation [264,265]. Lastly, SIRT1 regulates NER by deacetylating xeroderma pigmentosum proteins XPA and XPC, which, in turn, recruit other NER factors at the breaks for DNA repair [261]. SIRT2 is also implicated in mitotic progression and cell cycle regulation [266]. Regarding DNA damage pathways, SIRT2 modulates the mitotic methylation deposition of H4K20, which is essential for genome stability and DNA repair signaling [61] and directs the replication stress response through the deacetylation of kinase CDK9 [62]. SIRT3, SIRT4, and SIRT5 are mainly associated with mitochondrial metabolism [267], and by distinct pathways, they indirectly contribute to DNA stability through their participation in DDRs [107,268,269]. SIRT6 mediates H3K9 and H3K56 deacetylation, and SIRT6 deficiency leads to genomic instability and hypersensitivity to certain forms of genotoxic damage, thus interconnecting chromatin dynamics with metabolism and DNA repair [270,271]. In the BER pathway, SIRT6 acts as a regulator in a PARP1-dependent manner [272]. SIRT6 interacts with the enzymes MYH and APE1, and with the Rad9Rad1Hus1 checkpoint clamp, which stimulates BER [273]. Recently, SIRT6 has been identified as a double-strand break (DSB) sensor, since it recognizes DSBs,

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relocates to sites of damage, and activates downstream signaling for repair by triggering ATM recruitment, H2AX phosphorylation, and recruiting proteins of the HR and NHEJ pathways [274]. SIRT7 deacetylates H3K18 and affects the focal accumulation of the DDR factor 53BP1, thus reducing DSBs repair and leading to genome instability [275]. The activation of DDR signaling, can be achieved through a mechanism by which cells control their number of divisions through telomere shortening, leading to genomic destabilization [276]. This process results in replicative cell senescence. However, cells that deviate from this regulatory pathway can reach replicative immortality. Replicative immortality is a key feature in cancer and is defined as a hallmark of tumor development [139,140]. Several works have shown that sirtuins are essential in controlling senescence and extending cell life span. In humans SIRT1 and SIRT6 are the most studied chromatin remodeling factors that interact with telomere repeats, which are related to telomere integrity [277280]. The role of SIRT1 and SIRT6 in cell senescence has been elucidated by analysis of their expression in various cells and conditions [281284], by chemical inhibitors [36], and also by modulating their expression through overexpression [281,285287] or silencing [288,289]. Those distinct approaches have shown that SIRT1 and SIRT6 expression exhibit an inverse relationship with senescence, suggesting their participation in promoting this process. Localized at the telomeres, SIRT1 recruits WNR and promotes its deacetylation, which contributes to its function in maintaining genome stability [40]. Telomeric chromatin is maintained in a hypoacetylated, heterochromatic form via H3K9 deacetylation by the deacetylase SIRT6 [290]. Depletion of SIRT6 results in end-to-end chromosomal fusions and premature cellular senescence [277]. In these ways sirtuins participate in various DNA repair pathways, affecting genomic integrity and contributing to the maintenance of cell viability. Therefore they are key molecules in cancer development.

8.8 Sirtuins in reprogramming energy metabolism Otto Warburg was the first to observe metabolic reprogramming in tumor cells. He termed this phenomenon as “the Warburg effect,” a process where tumor cells use glycolysis in the cytosol to produce energy rather than the oxidative phosphorylation (OXPHOS)/tricarboxylic acid (TCA) cycle in the mitochondria as most normal cells do [291]. In addition, to acquire necessary nutrients for tumor development, tumors increase utilization of glutamine, an amino acid that is ultimately converted to ɑ-ketogluterate in the mitochondria as a substrate in the TCA cycle [292]. Furthermore, tumors increase utilization of the intermediates in glycolysis/OXPHOS/lipometabolism for biosynthesis and nicotinamide adenine dinucleotide phosphate (NADPH) production. This promotes alterations in metabolite-driven gene regulation and metabolic interactions with the tumor microenvironment [293]. Sirtuins can directly interact with metabolism-related genes and enzymes, and/or indirectly regulate upstream factors or pathways of glycolysis or OXPHOS, such as HIF-1/2, MYC, LKB1-5-AMPK, and p53 [294]. SIRT1 can positively regulate SIRT6 through a complex formed with FOXO3a and, also with NRF, both SIET1 and SIRT6 negatively regulate glycolysis, triglyceride synthesis, and lipid metabolism [295,296]. SIRT1 can also upregulate ATGL through FOXO1 activation, and therefore increase the rate of lipolysis [297]. SIRT1 indirectly interacts with major regulators, such as HIF-1/2, MYC, and LKB1-AMPK. SIRT1 deacetylates HIF-1α and HIF-2α, and thus triggers metabolic reprogramming. The deacetylation of HIF-2α and its increase in activity drive the expression of various transporters and enzymes that support the reductive and oxidative glutamine metabolism [298]. Alternatively, HIF-1α deacetylation inhibits its transcriptional activity decreasing the rate of glycolysis and promoting oxidative metabolism [223]. Another way that SIRT1 can inhibit the glycolysis is through the PGAM-1 deacetylation, reducing its catalytic activity [299]. The regulation of HIF-1α by SIRT2 occurs in a different manner than by SIRT1. HIF-1α induction by SIRT2 increases the expression of the glycolytic genes GLUT1 and LDHA, supporting tumor growth [56]. Moreover, the increased degradation of HIF-1α by SIRT2-mediated deacetylation causes an increase in the intracellular NAD1/NADH ratio [56]. These findings suggest that SIRT2-mediated HIF-1α deacetylation is critical for HIF-1α destabilization and the hypoxic response of cancer cells, and thus may affect their metabolism [300]. SIRT2 also regulates the activity of PGAM and G6PD, two key metabolic enzymes involved in glycolysis and the pentose phosphate pathway (PPP) [294]. SIRT2-mediated deacetylation of G6PD activates its enzymatic activity and stimulates PPP to supply cytosolic NADPH, thus promoting cell survival during oxidative stress [301]. SIRT2 also significantly increases OXPHOS and inhibits glycolysis via deacetylation of glycolytic enzymes, such as ALDOA, GAPDH, ENO1, and PGK1, which modulate cancer metabolism [302,303].

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SIRT2 is involved in fatty acid (FA) metabolism. SIRT2 deacetylates ACLY protein, causing its destabilization. ACLY destabilization leads to fatty synthesis inhibition, another alternative mechanism used by tumor cells to generate energy [55]. The absence of SIRT3 leads to overproduction of ROS, which causes stabilization of HIF-1ɑ in the nucleus and upregulation of its glycolytic targets, implicating SIRT3 as a potential regulator of the Warburg effect and tumor growth [82,174,221]. Another way that SIRT3 promotes upregulation of glycolytic genes is by interacting with LDHA [67]. Moreover, SIRT3 may protect mitochondrial DNA from oxidative damage via OGG1 deacetylation, which acts in DNA repair [300]. SIRT3 can modulate the OXPHOS/TCA cycle. SIRT3 increases mitochondrial oxygen consumption, by promoting GLUD1 expression to regulate glutamine-dependent oxidation [65,304]. GOT2 deacetylation by SIRT3 alters the malateaspartate NADH shuttle, which sustains high rates of glycolysis in tumor cells [304]. Moreover, when localized into the mitochondrial matrix, SIRT3 deacetylates and increases the activity of PDHA1, which increases the conversion of pyruvate into acetyl-CoA. This promotes the utilization of glucose and represses lactate production by tumor cells [305]. Furthermore, SIRT3 may lead to increased ATP production by deacetylating protein components of the electron transport chains [300,306308]. In addition, SIRT3 can regulate ROS production through modulation of SOD2, altering tumor cell metabolism [309,310]. Concerning FA oxidation, SIRT3 deacetylates long-chain acyl CoA and upregulates its enzymatic activity, creating an alternative route for energy production [299,311]. The mitochondrial sirtuin, SIRT4, also plays an important role in glutamine metabolism regulation via GLUD1, GDH1, and GLDH1 [312]. Reduction in utilization of glutamine by SIRT4 sensitizes tumors to glucose depletion [87]. In addition, SIRT4 can also function as a lipoamidase to diminish PDH activity, a hallmark of the Warburg effect [313]. SIRT4 catalyzes an alternative reaction involving the transfer of ADP-ribose from NAD1 to target substrates, causing inhibition of GDH, an enzyme that converts glutamate into ɑ-ketogluterate, and which, along with GLS1, drives glutamine catabolism to replenish the TCA cycle [87,314]. The ADP-ribosylation mediated by SIRT4 leads to GDH inactivation and inhibits mitochondrial glutamine metabolism [314]. Moreover, it was found that DNA damage induced a massive increased in SIRT4 expression, which triggers a shutdown of glutamine metabolism that is sufficient to cause cell cycle arrest [94]. In addition, SIRT4 can affect the transportation of ATP into the cytosol and ADP into the mitochondrial matrix, thereby providing substrates for ATP synthase [315]. SIRT4 also participates in FA oxidation, where it deacetylates malonyl-CoA decarboxylase, thus repressing its enzymatic activity and inhibiting the OXPHOS pathway [316]. The suppression of FA oxidation by SIRT4 can also occur through modulation of PPARα and AMPK activity [95,317]. In addition, SIRT4 is also responsible for leucine metabolism [294]. SIRT5 is also located in the mitochondria matrix and regulates the function of mitochondria. SIRT5 regulates cellular NADPH homeostasis and redox potential by deglutarylation of G6PDH [318]. SIRT5 desuccinylates PKM2, which contributes to the antioxidant response and suppresses tumor cell proliferation [103]. Moreover, the suppression of SIRT5 by CDK2 positively regulates aerobic glycolysis [319]. In addition, SIRT5 controls glucose oxidation by directly desuccinylating and repressing the activity of the enzymes PDH-E1 and DH [318,320]. SIRT5 also promotes IDH2 desuccinylation, thus regulating cellular NADPH homeostasis and redox potential [318]. SIRT5 can be translocated into the mitochondrial intermembrane space (MIS), where it deacetylates Cyt c, a protein of the MIS with a central function in the electron transport chain (ETC), as well as apoptosis initiation [191]. SIRT5 plays an important role in ROS detoxification, through desuccinylation and activation of Cu/Zn SOD1, a key antioxidant enzyme [98]. In addition, SIRT5 regulates lysine succinylation in the mitochondria and presents a mechanism for the inhibition of ketogenesis through HMGCS2 [300]. Regarding glutamine metabolism, SIRT5 uses its desuccinylate function to inhibit GLS, the enzyme that catalyzes the conversion of glutamine into glutamate in a reaction producing ammonia, thereby fostering glutamine utilization [205]. The participation of SIRT5 in FA oxidation involves the desuccinylation and activation of ECHA, an enzyme that catalyzes the formation of hydroxyacyl-CoA from enoyl-CoA, another alternative pathway to generate energy for tumor cells [321]. Interestingly, SIRT5 is the only sirtuin known to be involved in the urea cycle, where SIRT5 deacetylates, desuccinylates, and deglutarylates CPS1, increasing its activity. CPS1 is the enzyme that catalyzes the first step of the urea cycle for ammonia detoxification [237,322324].

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SIRT6 can repress multiple enzymes involved in the homeostatic control of glucose metabolism in cancer cells [111,325,326]. Lack of SIRT6 leads to an increase in glutamine metabolism and ribosomal gene expression [313]. Like SIRT1, SIRT2, and SIRT3, SIRT6 acts as a corepressor of HIF1ɑ transcriptional activity, deacetylating promoters of HIF1ɑ target genes and suppressing the expression of several key glycolytic genes, such as GLUT1, PFK1, PDK1A, and LDH [327]. In this way, SIRT6 maintains an efficient glucose flux into the TCA cycle under normal nutrient and oxygen conditions [328]. SIRT6 is also a MYC corepressor and the loss of SIRT6 results in derepressed expression of GLS1. This allows OXPHOS, but not glycolysis, to generate efficient ATP levels [300]. As mentioned before, SIRT6 is positively regulated by a complex between SIRT1 and FOXO3a, or with NRF1, all of which are involved in metabolic control [295,296]. This regulation results in the inhibition of two ratelimiting enzymes for gluconeogenesis, G6P and PEPCK-C. Increased expression of SIRT6 by p53 can contribute to inhibition of gluconeogenesis and repression of tumor growth [168]. In addition, the expression of SIRT6 can also negatively regulate triglyceride synthesis and fat metabolism [294]. SIRT7 also regulates HIF proteins by binding and decreasing the stability of both HIF-1α and HIF-2α, although the molecular mechanism involved in this regulation is not known [240]. Moreover, SIRT7 suppresses ribosomal gene expression acting as a corepressor of MYC in response to ER stress [329]. Nevertheless, the complex role of SIRT7 in cancer-associated metabolic reprogramming remains to be elucidated [313]. The ability of tumor cells to alter their metabolism and promote cell survival still has many unanswered questions. Sirtuins are involved in several steps of metabolic modulation, acting either directly or indirectly with genes or as cofactor for enzymes involved in metabolism. Sirtuins have been demonstrated to be key factors in this process and therefore deserving of further investigation in this field.

8.9 Sirtuins and cancer therapy Considering that one main role of sirtuins is to deacetylate histones, and that caloric restriction does not extend life span when sirtuins are deleted [144,330], the potential of sirtuins as a therapeutic target has been widely explored [167,331333]. Pharmacological manipulation of sirtuins began with the use of resveratrol (trans-3,40 ,5-trihydroxystilbene; Rsv), a compound found in grapes that confers protection against several age-related diseases, including cancer. Based on the hypothesis that sirtuins are critical proteins mediating caloric restriction and life span extension, Howitz et al. [334] identified multiple polyphenols as potential SIRT1 activators, and among them Rsv was the most potent. Currently, several SIRT1 activators and inhibitors have been described, with activators presenting more encouraging therapeutic potential than inhibitors [333]. Despite being the most promising as therapeutic targets, fewer activators were identified compared to inhibitors. Some activators have been described for SIRT1 [167,331], while many inhibitors have been reported for SIRT1 and SIRT2 [331333,335], and a small number for SIRT3 and SIRT5 [167]. In spite of the considerable efforts to develop these molecules, there has been limited success, mainly due to the lack of specificity, poor availability [331], and incomplete knowledge of downstream mechanisms [336]. This field of research is still in its infancy, and greater understanding of sirtuin function will have the potential to identify more promising therapeutic targets. Fig. 8.2 summarizes some of the SIRTs activators and inhibitors with reported effects on cancer. We have listed only the main activators/inhibitors and not their analogs. Also, we cited only the activators and inhibitors with scientific evidence of their roles in cancer, as follows: Resveratrol (Rsv)—Reduced tumorigenesis in SIRT11/2; p531/2 mice [247]. Unrelated to Rsv (SRT 1720)—Apoptosis in myeloma multiple cells via ATM/CHEk2 pathway [337]. Isoflavone/genistein—Binds to hormonal receptors in breast cancer cell lines upregulating SIRT1 to get lower oxidative stress and greater mitochondrial functionability [338]. Curcumin—Deacetylation of p53 and reduction of apoptosis [339]. Combrestatin analog YK-3237—Deacetylated both mutated and wild-type p53; inhibited the proliferation of TNBC cell lines carrying WTp53; arrested cell cycle in the G2/M phase in mtp53 TNBC cells by inducing apoptotic cell death [340]. Nicotinamide—Blocked proliferation and promoted apoptosis in leukemic cells and OSCC; inhibited the growth and viability in human prostate cells [341343]. Tenovin-1—Cytotoxic to Burkitt lymphoma and melanoma cells with wild-type p53 [344]. Tenovin-6—Reduced disease progression of CML [344]; eliminated cancer stem cell in uveal melanoma [345]. AGK2—Inhibited growth of glioblastoma multiforme [346]. Salermide—Inhibition of leukemic, colon, and lymphoma cell lines . Sirtinol—Inhibited viability of breast, lung, prostate, and oral cancer cells [342,343,348,349]. Cambinol—Induced apoptosis in BCL6-expressing Burkitt Lymphoma and reduced tumor growth in xenograft mouse; reduced neuroblastoma formation in N-Myc transgenic mice [350,351].

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FIGURE 8.2 Activators and inhibitors of sirtuins in cancer.

8.10 Concluding remarks It is clear in the current literature that sirtuins play a key role in multiple mechanisms of cancer progression. This chapter has summarized numerous research studies describing the role of specific sirtuins in each of the “hallmarks” of cancer. Many challenges remain to be addressed, for example, understanding the dual role of sirtuins as oncogenes or tumor suppressors, and identifying how modulation of sirtuin expression can be employed therapeutically. Certainly, the coming years should bring us abundant growth in sirtuin research, providing us with a better knowledge of their potential for understanding and treating several human diseases, including cancer.

References [1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin 2018;68(6):394424. [2] World Health Organization. WHO report on cancer: setting priorities, investing wisely and providing care for all. WHO; 2020. [3] Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer 2016;16(1):3542. [4] Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J 2007;404(1):113. [5] Sebastian C, Satterstrom FK, Haigis MC, Mostoslavsky R. From sirtuin biology to human diseases: an update. J Biol Chem 2012; 287(51):4244452. [6] Bosch-Presegue L, Vaquero A. The dual role of sirtuins in cancer. Genes Cancer 2011;2(6):64862. [7] Carafa V, Altucci L, Nebbioso A. Dual tumor suppressor and tumor promoter action of sirtuins in determining malignant phenotype. Front Pharmacol 2019;10:38. [8] Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer 2015;15(10):60824. [9] Roth M, Chen WY. Sorting out functions of sirtuins in cancer. Oncogene 2014;33(13):160920. [10] Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN, et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2006;2(3):e40. [11] Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001;107(2):14959. [12] Abdelmawgoud H, El Awady RR. Effect of Sirtuin 1 inhibition on matrix metalloproteinase 2 and Forkhead box O3a expression in breast cancer cells. Genes Dis 2017;4(4):2406. [13] Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y, et al. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 2006;8(9):102531. [14] Garcia-Rodriguez JL, Barbier-Torres L, Fernandez-Alvarez S, Gutierrez-de Juan V, Monte MJ, Halilbasic E, et al. SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling. Hepatology 2014;59(5):197283. [15] Yoon H, Shin SH, Shin DH, Chun YS, Park JW. Differential roles of Sirt1 in HIF-1alpha and HIF-2alpha mediated hypoxic responses. Biochem Biophys Res Commun 2014;444(1):3643. [16] Xie M, Liu M, He CS. SIRT1 regulates endothelial Notch signaling in lung cancer. PLoS One 2012;7(9):e45331. [17] Moore RL, Faller DV. SIRT1 represses estrogen-signaling, ligand-independent ERalpha-mediated transcription, and cell proliferation in estrogen-responsive breast cells. J Endocrinol 2013;216(3):27385. [18] Xu Z, Yang Y, Li B, Li Y, Xia K, Li X, et al. Checkpoint suppressor 1 suppresses transcriptional activity of ERalpha and breast cancer cell proliferation via deacetylase SIRT1. Cell Death Disease 2018;9(5):559.

II. Sirtuins and cancer

References

143

[19] Byles V, Chmilewski LK, Wang J, Zhu L, Forman LW, Faller DV, et al. Aberrant cytoplasm localization and protein stability of SIRT1 is regulated by PI3K/IGF-1R signaling in human cancer cells. Int J Biol Sci 2010;6(6):599612. [20] Yang Q, Wang B, Gao W, Huang S, Liu Z, Li W, et al. SIRT1 is downregulated in gastric cancer and leads to G1-phase arrest via NF-kappaB/Cyclin D1 signaling. Mol Cancer Res: MCR 2013;11(12):1497507. [21] Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One 2008;3(4):e2020. [22] Zhang S, Yang Y, Huang S, Deng C, Zhou S, Yang J, et al. SIRT1 inhibits gastric cancer proliferation and metastasis via STAT3/MMP-13 signaling. J Cell Physiol 2019;234(9):15395406. [23] Gao F, Cheng J, Shi T, Yeh ET. Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFkappaB-dependent transcription. Nat Cell Biol 2006;8(10):11717. [24] Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 2004;23(12):236980. [25] Lv C, Zhao G, Sun X, Wang P, Xie N, Luo J, et al. Acetylation of FOXM1 is essential for its transactivation and tumor growth stimulation. Oncotarget 2016;7(37):6036682. [26] Pediconi N, Guerrieri F, Vossio S, Bruno T, Belloni L, Schinzari V, et al. hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in response to DNA damage. Mol Cell Biol 2009;29(8):198998. [27] Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell 2008;32(1):1120. [28] Yuan J, Minter-Dykhouse K, Lou Z. A c-Myc-SIRT1 feedback loop regulates cell growth and transformation. J Cell Biol 2009; 185(2):20311. [29] Zhang Y, Zhang M, Dong H, Yong S, Li X, Olashaw N, et al. Deacetylation of cortactin by SIRT1 promotes cell migration. Oncogene 2009;28(3):44560. [30] Jin X, Wei Y, Xu F, Zhao M, Dai K, Shen R, et al. SIRT1 promotes formation of breast cancer through modulating Akt activity. J Cancer 2018;9(11):201223. [31] Joo HY, Yun M, Jeong J, Park ER, Shin HJ, Woo SR, et al. SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1alpha (HIF-1alpha) via direct interactions during hypoxia. Biochem Biophys Res Commun 2015;462(4):294300. [32] Li Y, Xu S, Li J, Zheng L, Feng M, Wang X, et al. SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1alphamediated mitochondrial biogenesis. Oncotarget 2016;7(20):2925574. [33] Simic P, Williams EO, Bell EL, Gong JJ, Bonkowski M, Guarente L. SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep 2013;3(4):117586. [34] Chen IC, Chiang WF, Huang HH, Chen PF, Shen YY, Chiang HC. Role of SIRT1 in regulation of epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis. Mol Cancer 2014;13:254. [35] Wong S, Weber JD. Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. Biochem J 2007;407(3):45160. [36] Rifai K, Judes G, Idrissou M, Daures M, Bignon YJ, Penault-Llorca F, et al. SIRT1-dependent epigenetic regulation of H3 and H4 histone acetylation in human breast cancer. Oncotarget 2018;9(55):3066178. [37] Jeong J, Juhn K, Lee H, Kim SH, Min BH, Lee KM, et al. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med 2007;39(1):813. [38] Fan W, Luo J. SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Mol Cell 2010;39(2):24758. [39] Yuan Z, Zhang X, Sengupta N, Lane WS, Seto E. SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol Cell 2007;27(1):14962. [40] Li K, Casta A, Wang R, Lozada E, Fan W, Kane S, et al. Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J Biol Chem 2008;283(12):75908. [41] Witherspoon M, Sandu D, Lu C, Wang K, Edwards R, Yeung A, et al. ETHE1 overexpression promotes SIRT1 and PGC1alpha mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer. Oncotarget 2019;10(40):400417. [42] Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 2008;283(41):2762835. [43] Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell 2007;28(1):91106. [44] Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 2010;285(44):3395970. [45] Yousafzai NA, Zhou Q, Xu W, Shi Q, Xu J, Feng L, et al. SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer. Cell Death Dis 2019;10(5):363. [46] Guo X, Williams JG, Schug TT, Li X. DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. J Biol Chem 2010;285(17):1322332. [47] Zhang L, Guo X, Zhang D, Fan Y, Qin L, Dong S. Upregulated miR-132 in Lgr5(1) gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway. Mol Carcinog 2017;56(9):202234. [48] Funato K, Hayashi T, Echizen K, Negishi L, Shimizu N, Koyama-Nasu R, et al. SIRT2-mediated inactivation of p73 is required for glioblastoma tumorigenicity. EMBO Rep 2018;19(11). [49] Dan L, Klimenkova O, Klimiankou M, Klusman JH, van den Heuvel-Eibrink MM, Reinhardt D, et al. The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells. Haematologica 2012; 97(4):5519. [50] Xu SN, Wang TS, Li X, Wang YP. SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation. Sci Rep 2016;6:32734. [51] Xu Y, Li F, Lv L, Li T, Zhou X, Deng CX, et al. Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase. Cancer Res 2014;74(13):363042.

II. Sirtuins and cancer

144

8. Sirtuins and the hallmarks of cancer

[52] Zhao D, Zou SW, Liu Y, Zhou X, Mo Y, Wang P, et al. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell 2013;23(4):46476. [53] Hoffmann G, Breitenbucher F, Schuler M, Ehrenhofer-Murray AE. A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent proapoptotic activity in non-small cell lung cancer. J Biol Chem 2014;289(8):520816. [54] Xie HJ, Jung KH, Nam SW. Overexpression of SIRT2 contributes tumor cell growth in hepatocellular carcinomas. Mol Cell Toxicol 2011;7:8. [55] Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell 2013;51(4):50618. [56] Seo KS, Park JH, Heo JY, Jing K, Han J, Min KN, et al. SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation. Oncogene 2015;34(11):135462. [57] Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, et al. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 2010;12(7):66575. [58] Li Y, Zhang M, Dorfman RG, Pan Y, Tang D, Xu L, et al. SIRT2 promotes the migration and invasion of gastric cancer through RAS/ ERK/JNK/MMP-9 pathway by increasing PEPCK1-related metabolism. Neoplasia 2018;20(7):74556. [59] Chen J, Chan AW, To KF, Chen W, Zhang Z, Ren J, et al. SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3beta/beta-catenin signaling. Hepatology 2013;57(6):228798. [60] Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 2011;20(4):48799. [61] Serrano L, Martinez-Redondo P, Marazuela-Duque A, Vazquez BN, Dooley SJ, Voigt P, et al. The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes Dev 2013;27(6):63953. [62] Zhang H, Park SH, Pantazides BG, Karpiuk O, Warren MD, Hardy CW, et al. SIRT2 directs the replication stress response through CDK9 deacetylation. Proc Natl Acad Sci U S A 2013;110(33):1354651. [63] Park SH, Ozden O, Liu G, Song HY, Zhu Y, Yan Y, et al. SIRT2-mediated deacetylation and tetramerization of pyruvate kinase directs glycolysis and tumor growth. Cancer Res 2016;76(13):380212. [64] Hu F, Sun X, Li G, Wu Q, Chen Y, Yang X, et al. Inhibition of SIRT2 limits tumour angiogenesis via inactivation of the STAT3/VEGFA signalling pathway. Cell Death Dis 2018;10(1):9. [65] Choi J, Koh E, Lee YS, Lee HW, Kang HG, Yoon YE, et al. Mitochondrial Sirt3 supports cell proliferation by regulating glutaminedependent oxidation in renal cell carcinoma. Biochem. Biophys Res Commun 2016;474(3):54753. [66] Chen S, Yang X, Yu M, Wang Z, Liu B, Liu M, et al. SIRT3 regulates cancer cell proliferation through deacetylation of PYCR1 in proline metabolism. Neoplasia 2019;21(7):66575. [67] Cui Y, Qin L, Wu J, Qu X, Hou C, Sun W, et al. SIRT3 enhances glycolysis and proliferation in SIRT3-expressing gastric cancer cells. PLoS One 2015;10(6):e0129834. [68] Li H, Feng Z, Wu W, Li J, Zhang J, Xia T. SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non-small cell lung cancer cells through deacetylation of NMNAT2. Int J Oncol 2013;43(5):142030. [69] Luo K, Huang W, Tang S. Sirt3 enhances glioma cell viability by stabilizing Ku70-BAX interaction. OncoTargets Ther 2018;11:755967. [70] Xu LX, Hao LJ, Ma JQ, Liu JK, Hasim A. SIRT3 promotes the invasion and metastasis of cervical cancer cells by regulating fatty acid synthase. Mol Cell Biochem 2020;464(1-2):1120. [71] Allison SJ, Milner J. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle 2007;6(21):266977. [72] Wang L, Wang WY, Cao LP. SIRT3 inhibits cell proliferation in human gastric cancer through down-regulation of Notch-1. Int J Clin Exp Med 2015;8(4):526371. [73] Zhang YY, Zhou LM. Sirt3 inhibits hepatocellular carcinoma cell growth through reducing Mdm2-mediated p53 degradation. Biochem Biophys Res Commun 2012;423(1):2631. [74] Cheng Y, Ren X, Gowda AS, Shan Y, Zhang L, Yuan YS, et al. Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress. Cell Death Dis 2013;4:e731. [75] Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014;53(4):53448. [76] Xu L, Li Y, Zhou L, Dorfman RG, Liu L, Cai R, et al. SIRT3 elicited an anti-Warburg effect through HIF1alpha/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis. Cancer Med 2019;8(5):238091. [77] Liu H, Li S, Liu X, Chen Y, Deng H. SIRT3 overexpression inhibits growth of kidney tumor cells and enhances mitochondrial biogenesis. J Proteome Res 2018;17(9):314352. [78] Inuzuka H, Gao D, Finley LW, Yang W, Wan L, Fukushima H, et al. Acetylation-dependent regulation of Skp2 function. Cell 2012;150 (1):17993. [79] Lee JJ, van de Ven RAH, Zaganjor E, Ng MR, Barakat A, Demmers J, et al. Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3. Proc Natl Acad Sci U S A 2018;115(27):705762. [80] Jacobs KM, Pennington JD, Bisht KS, Aykin-Burns N, Kim HS, Mishra M, et al. SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. Int J Biol Sci 2008;4(5):2919. [81] Kim YS, Gupta Vallur P, Jones VM, Worley BL, Shimko S, Shin DH, et al. Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells. Oncogene 2020;39(8):161933. [82] Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell 2011;19(3):41628. [83] Wei L, Zhou Y, Dai Q, Qiao C, Zhao L, Hui H, et al. Oroxylin A induces dissociation of hexokinase II from the mitochondria and inhibits glycolysis by SIRT3-mediated deacetylation of cyclophilin D in breast carcinoma. Cell Death Dis 2013;4:e601. [84] Liu M, Wang Z, Ren M, Yang X, Liu B, Qi H, et al. SIRT4 regulates PTEN stability through IDE in response to cellular stresses. FASEB J: Off Publ Federation Am Soc Exp Biol 2019;33(4):553547. [85] Zhang J, Wang G, Mao Q, Li S, Xiong W, Lin Y, et al. Glutamate dehydrogenase (GDH) regulates bioenergetics and redox homeostasis in human glioma. Oncotarget 2016;5:112. Retrieved from https://www.oncotarget.com/article/7657/.

II. Sirtuins and cancer

References

145

[86] Nakahara Y, Yamasaki M, Sawada G, Miyazaki Y, Makino T, Takahashi T, et al. Downregulation of SIRT4 expression is associated with poor prognosis in esophageal squamous cell carcinoma. Oncology 2016;90(6):34755. [87] Jeong SM, Lee A, Lee J, Haigis MC. SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J Biol Chem 2014;289(7):413544. [88] Chen Z, Lin J, Feng S, Chen X, Huang H, Wang C, et al. SIRT4 inhibits the proliferation, migration, and invasion abilities of thyroid cancer cells by inhibiting glutamine metabolism. OncoTargets Ther 2019;12:2397408. [89] Fu L, Dong Q, He J, Wang X, Xing J, Wang E, et al. SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway. Oncogene 2017;36(19):272436. [90] Miyo M, Yamamoto H, Konno M, Colvin H, Nishida N, Koseki J, et al. Tumour-suppressive function of SIRT4 in human colorectal cancer. Br J Cancer 2015;113(3):4929. [91] Hu Y, Lin J, Lin Y, Chen X, Zhu G, Huang G. Overexpression of SIRT4 inhibits the proliferation of gastric cancer cells through cell cycle arrest. Oncol Lett 2019;17(2):21716. [92] Wang YS, Du L, Liang X, Meng P, Bi L, Wang YL, et al. Sirtuin 4 depletion promotes hepatocellular carcinoma tumorigenesis through regulating adenosine-monophosphate-activated protein kinase alpha/mammalian target of rapamycin axis in mice. Hepatology 2019; 69(4):161431. [93] Wang Y, Guo Y, Gao J, Yuan X. Tumor-suppressive function of SIRT4 in neuroblastoma through mitochondrial damage. Cancer Manag Res 2018;10:5591603. [94] Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013;23(4):45063. [95] Ho L, Titus AS, Banerjee KK, George S, Lin W, Deota S, et al. SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK. Aging 2013;5(11):83549. [96] Xing J, Li J, Fu L, Gai J, Guan J, Li Q. SIRT4 enhances the sensitivity of ER-positive breast cancer to tamoxifen by inhibiting the IL-6/ STAT3 signal pathway. Cancer Med 2019;8(16):708697. [97] Zhang R, Wang C, Tian Y, Yao Y, Mao J, Wang H, et al. SIRT5 promotes hepatocellular carcinoma progression by regulating mitochondrial apoptosis. J Cancer 2019;10(16):387182. [98] Lin ZF, Xu HB, Wang JY, Lin Q, Ruan Z, Liu FB, et al. SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochem Biophys Res Commun 2013;441(1):1915. [99] Lu W, Zuo Y, Feng Y, Zhang M. SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer. Tumour Biol: J Int Soc Oncodev Biol Med 2014;35(11):10699705. [100] Wang YQ, Wang HL, Xu J, Tan J, Fu LN, Wang JL, et al. Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner. Nat Commun 2018;9(1):545. [101] Chang L, Xi L, Liu Y, Liu R, Wu Z, Jian Z. SIRT5 promotes cell proliferation and invasion in hepatocellular carcinoma by targeting E2F1. Mol Med Rep 2018;17(1):3429. [102] Shi L, Yan H, An S, Shen M, Jia W, Zhang R, et al. SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. Mol Oncol 2019;13(2):35875. [103] Xiangyun Y, Xiaomin N, Linping G, Yunhua X, Ziming L, Yongfeng Y, et al. Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth. Oncotarget 2017;8(4):698493. [104] Greene KS, Lukey MJ, Wang X, Blank B, Druso JE, Lin MJ, et al. SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis. Proc Natl Acad Sci U S A 2019;. [105] Yang X, Wang Z, Li X, Liu B, Liu M, Liu L, et al. SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation. Cancer Res 2018; 78(2):37286. [106] Ma Y, Qi Y, Wang L, Zheng Z, Zhang Y, Zheng J. SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis. Free Radic Biol Med 2019;134:45867. [107] Chen XF, Tian MX, Sun RQ, Zhang ML, Zhou LS, Jin L, et al. SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer. EMBO Rep 2018;19(5). [108] Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaBdependent gene expression and organismal life span. Cell 2009;136(1):6274. [109] Ran LK, Chen Y, Zhang ZZ, Tao NN, Ren JH, Zhou L, et al. SIRT6 overexpression potentiates apoptosis evasion in hepatocellular carcinoma via BCL2-associated X protein-dependent apoptotic pathway. Clin Cancer Res: Off J Am Assoc Cancer Res 2016;22(13):337282. [110] Ming M, Han W, Zhao B, Sundaresan NR, Deng CX, Gupta MP, et al. SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer Res 2014;74(20):592533. [111] Sebastian C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 2012;151(6):118599. [112] Wang J, Sheng Z, Cai Y. SIRT6 overexpression inhibits HIF1alpha expression and its impact on tumor angiogenesis in lung cancer. Int J Clin Exp Pathol 2018;11(6):29407. [113] Kugel S, Sebastian C, Fitamant J, Ross KN, Saha SK, Jain E, et al. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell 2016;165(6):140115. [114] Ouyang L, Yi L, Li J, Yi S, Li S, Liu P, et al. SIRT6 overexpression induces apoptosis of nasopharyngeal carcinoma by inhibiting NF-kappaB signaling. OncoTargets Ther 2018;11:761324. [115] Chen X, Hao B, Liu Y, Dai D, Han G, Li Y, et al. The histone deacetylase SIRT6 suppresses the expression of the RNA-binding protein PCBP2 in glioma. Biochem Biophys Res Commun 2014;446(1):3649. [116] Han Z, Liu L, Liu Y, Li S. Sirtuin SIRT6 suppresses cell proliferation through inhibition of Twist1 expression in non-small cell lung cancer. Int J Clin Exp Pathol 2014;7(8):477481. [117] Zhang ZG, Qin CY. Sirt6 suppresses hepatocellular carcinoma cell growth via inhibiting the extracellular signalregulated kinase signaling pathway. Mol Med Rep 2014;9(3):8828.

II. Sirtuins and cancer

146

8. Sirtuins and the hallmarks of cancer

[118] Zhang J, Yin XJ, Xu CJ, Ning YX, Chen M, Zhang H, et al. The histone deacetylase SIRT6 inhibits ovarian cancer cell proliferation via down-regulation of Notch 3 expression. Eur Rev Med Pharmacol Sci 2015;19(5):81824. [119] Bhardwaj A, Das S. SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions. Proc Natl Acad Sci U S A 2016;113(5):E53847. [120] Bauer I, Grozio A, Lasiglie D, Basile G, Sturla L, Magnone M, et al. The NAD 1 -dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2 1 responses. J Biol Chem 2012;287(49):4092437. [121] Feng XX, Luo J, Liu M, Yan W, Zhou ZZ, Xia YJ, et al. Sirtuin 6 promotes transforming growth factor-beta1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence. Cancer Sci 2015;106(5):55966. [122] Hu JQ, Deng F, Hu XP, Zhang W, Zeng XC, Tian XF. Histone deacetylase SIRT6 regulates chemosensitivity in liver cancer cells via modulation of FOXO3 activity. Oncol Rep 2018;40(6):363544. [123] Yu H, Ye W, Wu J, Meng X, Liu RY, Ying X, et al. Overexpression of sirt7 exhibits oncogenic property and serves as a prognostic factor in colorectal cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 2014;20(13):343445. [124] Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 2012;487(7405):11418. [125] Zhao J, Wozniak A, Adams A, Cox J, Vittal A, Voss J, et al. SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway. J Exp Clin Cancer Res: CR 2019;38(1):252. [126] Zhang S, Chen P, Huang Z, Hu X, Chen M, Hu S, et al. Sirt7 promotes gastric cancer growth and inhibits apoptosis by epigenetically inhibiting miR-34a. Sci Rep 2015;5:9787. [127] Wang HL, Lu RQ, Xie SH, Zheng H, Wen XM, Gao X, et al. SIRT7 exhibits oncogenic potential in human ovarian cancer cells. Asian Pac J Cancer Prev: APJCP 2015;16(8):35737. [128] Tsai YC, Greco TM, Cristea IM. Sirtuin 7 plays a role in ribosome biogenesis and protein synthesis. Mol Cell Proteom: MCP 2014;13(1):7383. [129] Wei W, Jing ZX, Ke Z, Yi P. Sirtuin 7 plays an oncogenic role in human osteosarcoma via downregulating CDC4 expression. Am J Cancer Res 2017;7(9):1788803. [130] Ding M, Jiang CY, Zhang Y, Zhao J, Han BM, Xia SJ. SIRT7 depletion inhibits cell proliferation and androgen-induced autophagy by suppressing the AR signaling in prostate cancer. J Exp Clin Cancer Res: CR 2020;39(1):28. [131] Chen KL, Li L, Yang FX, Li CM, Wang YR, Wang GL. SIRT7 depletion inhibits cell proliferation, migration, and increases drug sensitivity by activating p38MAPK in breast cancer cells. J Cell Physiol 2018;233(9):676778. [132] Li H, Tian Z, Qu Y, Yang Q, Guan H, Shi B, et al. SIRT7 promotes thyroid tumorigenesis through phosphorylation and activation of Akt and p70S6K1 via DBC1/SIRT1 axis. Oncogene 2019;38(3):34559. [133] Mu P, Liu K, Lin Q, Yang W, Liu D, Lin Z, et al. Sirtuin 7 promotes glioma proliferation and invasion through activation of the ERK/STAT3 signaling pathway. Oncol Lett 2019;17(2):144552. [134] Mo Y, Lin R, Liu P, Tan M, Xiong Y, Guan KL, et al. SIRT7 deacetylates DDB1 and suppresses the activity of the CRL4 E3 ligase complexes. The FEBS J 2017;284(21):361936. [135] Lee HS, Jung W, Lee E, Chang H, Choi JH, Kim HG, et al. SIRT7, H3K18ac, and ELK4 immunohistochemical expression in hepatocellular carcinoma. J Pathol Transl Med 2016;50(5):33744. [136] Malik S, Villanova L, Tanaka S, Aonuma M, Roy N, Berber E, et al. SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors. Sci Rep 2015;5:9841. [137] Tang X, Shi L, Xie N, Liu Z, Qian M, Meng F, et al. SIRT7 antagonizes TGF-beta signaling and inhibits breast cancer metastasis. Nat Commun 2017;8(1):318. [138] Song C, Hotz-Wagenblatt A, Voit R, Grummt I. SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability. Genes Dev 2017;31(13):137081. [139] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):5770. [140] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):64674. [141] Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, et al. Sustained proliferation in cancer: mechanisms and novel therapeutic targets. Semcancer Biol 2015;35(Suppl.):S2554. [142] Holloway KR, Calhoun TN, Saxena M, Metoyer CF, Kandler EF, Rivera CA, et al. SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling. Proc Natl Acad Sci U S A 2010;107(20):921621. [143] O’Callaghan C, Vassilopoulos A. Sirtuins at the crossroads of stemness, aging, and cancer. Aging Cell 2017;16(6):120818. [144] Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305(5682):3902. [145] Sundaresan NR, Vasudevan P, Zhong L, Kim G, Samant S, Parekh V, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med 2012;18(11):164350. [146] Nakagawa T, Guarente L. Sirtuins at a glance. J Cell Sci 2011;124(Pt 6):8338. [147] Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 2011;11(11):76174. [148] Simmons Jr. GE, Pandey S, Nedeljkovic-Kurepa A, Saxena M, Wang A, Pruitt K. Frizzled 7 expression is positively regulated by SIRT1 and beta-catenin in breast cancer cells. PLoS One 2014;9(6):e98861. [149] Ramakrishnan G, Davaakhuu G, Kaplun L, Chung WC, Rana A, Atfi A, et al. Sirt2 deacetylase is a novel AKT binding partner critical for AKT activation by insulin. J Biol Chem 2014;289(9):605466. [150] Yu J, Qin B, Wu F, Qin S, Nowsheen S, Shan S, et al. Regulation of serine-threonine kinase Akt activation by NAD(1)-dependent deacetylase SIRT7. Cell Rep 2017;18(5):122940. [151] Quan Y, Wang N, Chen Q, Xu J, Cheng W, Di M, et al. SIRT3 inhibits prostate cancer by destabilizing oncoprotein c-MYC through regulation of the PI3K/Akt pathway. Oncotarget 2015;6(28):26494507. [152] Ghosh HS, McBurney M, Robbins PD. SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One 2010;5(2):e9199. [153] Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2013;153(4):84054.

II. Sirtuins and cancer

References

147

[154] Costa-Machado LF, Martin-Hernandez R, Sanchez-Luengo MA, Hess K, Vales-Villamarin C, Barradas M, et al. Sirt1 protects from K-Ras-driven lung carcinogenesis. EMBO Rep 2018;19(9). [155] Cheng D, Zhao L, Xu Y, Ou R, Li G, Yang H, et al. K-Ras promotes the non-small lung cancer cells survival by cooperating with sirtuin 1 and p27 under ROS stimulation. Tumour Biol: J Int Soc Oncodev Biol Med 2015;36(9):722132. [156] Cheng Z, Li X, Hou S, Wu Y, Sun Y, Liu B. K-Ras-ERK1/2 accelerates lung cancer cell development via mediating H3(K18ac) through the MDM2-GCN5-SIRT7 axis. Pharm Biol 2019;57(1):7019. [157] Zhang X, Khan S, Jiang H, Antonyak MA, Chen X, Spiegelman NA, et al. Identifying the functional contribution of the defatty-acylase activity of SIRT6. Nat Chem Biol 2016;12(8):61420. [158] Amin A, Karpowicz PA, Carey TE, Arbiser J, Nahta R, Chen ZG, et al. Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds. Semcancer Biol 2015;35(Suppl.):S5577. [159] Tian J, Yuan L. Sirtuin 6 inhibits colon cancer progression by modulating PTEN/AKT signaling. Biomed Pharmacother 2018;106:10916. [160] Zhou ZW, Li XX, He ZX, Pan ST, Yang Y, Zhang X, et al. Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTORmediated pathways by plumbagin in human prostate cancer cells. Drug Des Dev Ther 2015;9:151154. [161] Jing H, Hu J, He B, Negron Abril YL, Stupinski J, Weiser K, et al. A SIRT2-selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anticancer activity. Cancer Cell 2016;29(4):607. [162] Menssen A, Hydbring P, Kapelle K, Vervoorts J, Diebold J, Luscher B, et al. The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. Proc Natl Acad Sci U S A 2012;109(4):E18796. [163] Brandl L, Zhang Y, Kirstein N, Sendelhofert A, Boos SL, Jung P, et al. Targeting c-MYC through interference with NAMPT and SIRT1 and their association to oncogenic drivers in murine serrated intestinal tumorigenesis. Neoplasia 2019;21(10):97488. [164] Zwaans BM, Lombard DB. Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming. Dis Model Mech 2014;7(9):102332. [165] Kim EJ, Kho JH, Kang MR, Um SJ. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol Cell 2007;28(2):27790. [166] van Leeuwen IM, Higgins M, Campbell J, McCarthy AR, Sachweh MC, Navarro AM, et al. Modulation of p53 C-terminal acetylation by mdm2, p14ARF, and cytoplasmic SirT2. Mol Cancer Ther 2013;12(4):47180. [167] George J, Ahmad N. Mitochondrial sirtuins in cancer: emerging roles and therapeutic potential. Cancer Res 2016;76(9):25006. [168] Zhang P, Tu B, Wang H, Cao Z, Tang M, Zhang C, et al. Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc Natl Acad Sci U S A 2014;111(29):106849. [169] Yeung YT, Guerrero-Castilla A, Cano M, Munoz MF, Ayala A, Arguelles S. Dysregulation of the Hippo pathway signaling in aging and cancer. Pharmacol Res 2019;143:15165. [170] Yuan F, Xie Q, Wu J, Bai Y, Mao B, Dong Y, et al. MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation. J Biol Chem 2011;286(9):69405. [171] Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, et al. A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. Mol Cell 2011;42(5):68999. [172] Shamas-Din A, Kale J, Leber B, Andrews DW. Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb Perspect Biol 2013;5(4): a008714. [173] Fernald K, Kurokawa M. Evading apoptosis in cancer. Trends Cell Biol 2013;23(12):62033. [174] Alhazzazi TY, Kamarajan P, Verdin E, Kapila YL. Sirtuin-3 (SIRT3) and the hallmarks of cancer. Genes Cancer 2013;4(3-4):16471. [175] Peck B, Chen CY, Ho KK, Di Fruscia P, Myatt SS, Coombes RC, et al. SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther 2010;9(4):84455. [176] Van Meter M, Mao Z, Gorbunova V, Seluanov A. SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells. Cell Cycle 2011;10(18):31538. [177] Costa-Machado LF, Fernandez-Marcos PJ. The sirtuin family in cancer. Cell Cycle 2019;18(18):216496. [178] Voelter-Mahlknecht S, Mahlknecht U. The sirtuins in the pathogenesis of cancer. Clin Epigenetics 2010;1(34):7183. [179] Fong Y, Lin YC, Wu CY, Wang HM, Lin LL, Chou HL, et al. The antiproliferative and apoptotic effects of sirtinol, a sirtuin inhibitor on human lung cancer cells by modulating Akt/beta-catenin-Foxo3a axis. Sci World J 2014;2014:937051. [180] Bringman-Rodenbarger LR, Guo AH, Lyssiotis CA, Lombard DB. Emerging roles for SIRT5 in metabolism and cancer. Antioxid Redox Signal 2018;28(8):67790. [181] Yu W, Cui X, Wan Z, Yu Y, Liu X, Jin L. Silencing forkhead box M1 promotes apoptosis and autophagy through SIRT7/mTOR/IGF2 pathway in gastric cancer cells. J Cell Biochem 2018;119(11):90908. [182] Ni Z, Wang B, Dai X, Ding W, Yang T, Li X, et al. HCC cells with high levels of Bcl-2 are resistant to ABT-737 via activation of the ROSJNK-autophagy pathway. Free Radic Biol Med 2014;70:194203. [183] Li S, Banck M, Mujtaba S, Zhou MM, Sugrue MM, Walsh MJ. p53-Induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS One 2010;5(5):e10486. [184] Sawada M, Sun W, Hayes P, Leskov K, Boothman DA, Matsuyama S. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol 2003;5(4):3209. [185] Xiong Y, Wang M, Zhao J, Han Y, Jia L. Sirtuin 3: a Janus face in cancer (review). Int J Oncol 2016;49(6):222735. [186] Alhazzazi TY, Kamarajan P, Verdin E, Kapila YL. SIRT3 and cancer: tumor promoter or suppressor? Biochim Biophys Acta 2011;1816(1):808. [187] Ansari A, Rahman MS, Saha SK, Saikot FK, Deep A, Kim KH. Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell 2017;16(1):416. [188] Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, et al. Nutrient-sensitive mitochondrial NAD 1 levels dictate cell survival. Cell 2007;130(6):1095107. [189] Shi JX, Wang QJ, Li H, Huang Q. SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis. Exp Ther Med 2017;13(1):3428.

II. Sirtuins and cancer

148

8. Sirtuins and the hallmarks of cancer

[190] Liu B, Che W, Xue J, Zheng C, Tang K, Zhang J, et al. SIRT4 prevents hypoxia-induced apoptosis in H9c2 cardiomyoblast cells. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol 2013;32(3):65562. [191] Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol 2008;382(3):790801. [192] Feng J, Yan PF, Zhao HY, Zhang FC, Zhao WH, Feng M. SIRT6 suppresses glioma cell growth via induction of apoptosis, inhibition of oxidative stress and suppression of JAK2/STAT3 signaling pathway activation. Oncol Rep 2016;35(3):1395402. [193] Zhang C, Yu Y, Huang Q, Tang K. SIRT6 regulates the proliferation and apoptosis of hepatocellular carcinoma via the ERK1/2 signaling pathway. Mol Med Rep 2019;20(2):157582. [194] Tang M, Li Z, Zhang C, Lu X, Tu B, Cao Z, et al. SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair. Sci Adv 2019;5(3):eaav1118. [195] Paredes S, Villanova L, Chua KF. Molecular pathways: emerging roles of mammalian Sirtuin SIRT7 in cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 2014;20(7):17416. [196] Zhao E, Hou J, Ke X, Abbas MN, Kausar S, Zhang L, et al. The roles of sirtuin family proteins in cancer progression. Cancers 2019; 11(12). [197] Peixoto P, Grandvallet C, Feugeas JP, Guittaut M, Hervouet E. Epigenetic control of autophagy in cancer cells: a key process for cancerrelated phenotypes. Cells 2019;8(12). [198] Nemoto S, Fergusson MM, Finkel T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 2004; 306(5704):21058. [199] Lee IH. Mechanisms and disease implications of sirtuin-mediated autophagic regulation. Exp Mol Med 2019;51(9):111. [200] Qiu G, Li X, Che X, Wei C, He S, Lu J, et al. SIRT1 is a regulator of autophagy: implications in gastric cancer progression and treatment. FEBS Lett 2015;589(16):203442. [201] Liu G, Park SH, Imbesi M, Nathan WJ, Zou X, Zhu Y, et al. Loss of NAD-dependent protein deacetylase sirtuin-2 alters mitochondrial protein acetylation and dysregulates mitophagy. Antioxid Redox Signal 2017;26(15):84963. [202] Qiao A, Wang K, Yuan Y, Guan Y, Ren X, Li L, et al. Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia. Oncotarget 2016;7(28):43390400. [203] Guedouari H, Daigle T, Scorrano L, Hebert-Chatelain E. Sirtuin 5 protects mitochondria from fragmentation and degradation during starvation. Biochim Biophys Acta Mol Cell Res 2017;1864(1):16976. [204] Huang N, Liu Z, Zhu J, Cui Z, Li Y, Yu Y, et al. Sirtuin 6 plays an oncogenic role and induces cell autophagy in esophageal cancer cells. Tumour Biol: J Int Soc Oncodev Biol Med 2017;39(6) 1010428317708532. [205] Polletta L, Vernucci E, Carnevale I, Arcangeli T, Rotili D, Palmerio S, et al. SIRT5 regulation of ammonia-induced autophagy and mitophagy. Autophagy 2015;11(2):25370. [206] Garva R, Thepmalee C, Yasamut U, Sudsaward S, Guazzelli A, Rajendran R, et al. Sirtuin family members selectively regulate autophagy in osteosarcoma and mesothelioma cells in response to cellular stress. Front Oncol 2019;9:949. [207] Wang L, Guo W, Ma J, Dai W, Liu L, Guo S, et al. Aberrant SIRT6 expression contributes to melanoma growth: role of the autophagy paradox and IGF-AKT signaling. Autophagy 2018;14(3):51833. [208] Wu D, Li Y, Zhu KS, Wang H, Zhu WG. Advances in cellular characterization of the sirtuin isoform, SIRT7. Front Endocrinol 2018;9:652. [209] Galli M, Van Gool F, Leo O. Sirtuins and inflammation: friends or foes? Biochem. Pharmacol 2011;81(5):56976. [210] Horio Y, Hayashi T, Kuno A, Kunimoto R. Cellular and molecular effects of sirtuins in health and disease. Clin Sci (Lond) 2011; 121(5):191203. [211] Hayden MS, West AP, Ghosh S. NF-kappaB and the immune response. Oncogene 2006;25(51):675880. [212] Lappas M. Anti-inflammatory properties of sirtuin 6 in human umbilical vein endothelial cells. Mediators Inflamm 2012;2012:597514. [213] Yang H, Zhou L, Shi Q, Zhao Y, Lin H, Zhang M, et al. SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J 2015;34(8):111025. [214] Zeng H, Chi H. Metabolic control of regulatory T cell development and function. Trends Immunol 2015;36(1):312. [215] Yoshizaki T, Schenk S, Imamura T, Babendure JL, Sonoda N, Bae EJ, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab 2010;298(3):E41928. [216] Kong S, Kim SJ, Sandal B, Lee SM, Gao B, Zhang DD, et al. The type III histone deacetylase Sirt1 protein suppresses p300-mediated histone H3 lysine 56 acetylation at Bclaf1 promoter to inhibit T cell activation. J Biol Chem 2011;286(19):1696775. [217] Aronoff DM, Canetti C, Peters-Golden M. Prostaglandin E2 inhibits alveolar macrophage phagocytosis through an E-prostanoid 2 receptor-mediated increase in intracellular cyclic AMP. J Immunol 2004;173(1):55965. [218] Zhang R, Chen HZ, Liu JJ, Jia YY, Zhang ZQ, Yang RF, et al. SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J Biol Chem 2010;285(10):7097110. [219] Bhalla S, Gordon LI. Functional characterization of NAD dependent de-acetylases SIRT1 and SIRT2 in B-Cell Chronic Lymphocytic Leukemia (CLL). Cancer Biol Ther 2016;17(3):3009. [220] Koyama T, Kume S, Koya D, Araki S, Isshiki K, Chin-Kanasaki M, et al. SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells. Free Radic Biol Med 2011;51(6):125867. [221] Bell EL, Emerling BM, Ricoult SJ, Guarente L. SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene 2011;30(26):298696. [222] Kondo Y, Arii S, Mori A, Furutani M, Chiba T, Imamura M. Enhancement of angiogenesis, tumor growth, and metastasis by transfection of vascular endothelial growth factor into LoVo human colon cancer cell line. Clin Cancer Res: Off J Am Assoc Cancer Res 2000; 6(2):62230. [223] Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 2012;13(4):22538. [224] Laemmle A, Lechleiter A, Roh V, Schwarz C, Portmann S, Furer C, et al. Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1alpha protein under hypoxic conditions. PLoS One 2012;7(3):e33433.

II. Sirtuins and cancer

References

149

[225] Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxiainducible factor 1alpha. Mol Cell 2010;38(6):86478. [226] Pellegrini L, Pucci B, Villanova L, Marino ML, Marfe G, Sansone L, et al. SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH. Cell Death Differ 2012;19(11):181525. [227] Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A 2004;101(27):100427. [228] Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 2004;116(4):55163. [229] Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, et al. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 2007;21(20):264458. [230] Guarani V, Deflorian G, Franco CA, Kruger M, Phng LK, Bentley K, et al. Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature 2011;473(7346):2348. [231] Jiang BH, Liu LZ. AKT signaling in regulating angiogenesis. Curr Cancer Drug Targets 2008;8(1):1926. [232] Okumura N, Yoshida H, Kitagishi Y, Murakami M, Nishimura Y, Matsuda S. PI3K/AKT/PTEN signaling as a molecular target in leukemia angiogenesis. Adv Hematol 2012;2012:843085. [233] Wallerath T, Li H, Godtel-Ambrust U, Schwarz PM, Forstermann U. A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide: Biol Chem 2005;12(2):97104. [234] Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res 2008;102(6):70310. [235] Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002;21(13):20008. [236] Tseng AH, Wu LH, Shieh SS, Wang DL. SIRT3 interactions with FOXO3 acetylation, phosphorylation and ubiquitinylation mediate endothelial cell responses to hypoxia. Biochem J 2014;464(1):15768. [237] Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 2011;334(6057):8069. [238] Kunhiraman H, Edatt L, Thekkeveedu S, Poyyakkara A, Raveendran V, Kiran MS, et al. 2-Deoxy glucose modulates expression and biological activity of VEGF in a SIRT-1 dependent mechanism. J Cell Biochem 2017;118(2):25262. [239] Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 2005; 280(22):2131320. [240] Hubbi ME, Hu H, Kshitiz, Gilkes DM, Semenza GL. Sirtuin-7 inhibits the activity of hypoxia-inducible factors. J Biol Chem 2013; 288(29):2076875. [241] He SJ, Xiang CQ, Zhang Y, Lu XT, Chen HW, Xiong LX. Recent progress on the effects of microRNAs and natural products on tumor epithelial-mesenchymal transition. OncoTargets Ther 2017;10:343551. [242] Byles V, Zhu L, Lovaas JD, Chmilewski LK, Wang J, Faller DV, et al. SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene 2012;31(43):461929. [243] Jang KY, Kim KS, Hwang SH, Kwon KS, Kim KR, Park HS, et al. Expression and prognostic significance of SIRT1 in ovarian epithelial tumours. Pathology 2009;41(4):36671. [244] Jang SH, Min KW, Paik SS, Jang KS. Loss of SIRT1 histone deacetylase expression associates with tumour progression in colorectal adenocarcinoma. J Clin Pathol 2012;65(8):7359. [245] Kabra N, Li Z, Chen L, Li B, Zhang X, Wang C, et al. SirT1 is an inhibitor of proliferation and tumor formation in colon cancer. J Biol Chem 2009;284(27):1821017. [246] Stunkel W, Peh BK, Tan YC, Nayagam VM, Wang X, Salto-Tellez M, et al. Function of the SIRT1 protein deacetylase in cancer. Biotechnol J 2007;2(11):13608. [247] Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 2008;14(4):31223. [248] Wu M, Wei W, Xiao X, Guo J, Xie X, Li L, et al. Expression of SIRT1 is associated with lymph node metastasis and poor prognosis in both operable triple-negative and non-triple-negative breast cancer. Med Oncol 2012;29(5):32409. [249] Dong XC, Jing LM, Wang WX, Gao YX. Down-regulation of SIRT3 promotes ovarian carcinoma metastasis. Biochem Biophys Res Commun 2016;475(3):24550. [250] Li R, Quan Y, Xia W. SIRT3 inhibits prostate cancer metastasis through regulation of FOXO3A by suppressing Wnt/beta-catenin pathway. Exp Cell Res 2018;364(2):14351. [251] Zeng X, Wang N, Zhai H, Wang R, Wu J, Pu W. SIRT3 functions as a tumor suppressor in hepatocellular carcinoma. Tumour Biol: J Int Soc Oncodev Biol Med 2017;39(3) 1010428317691178. [252] Zhou W, Ni TK, Wronski A, Glass B, Skibinski A, Beck A, et al. The SIRT2 deacetylase stabilizes slug to control malignancy of basallike breast cancer. Cell Rep 2016;17(5):130217. [253] Shi Q, Liu T, Zhang X, Geng J, He X, Nu M, et al. Decreased sirtuin 4 expression is associated with poor prognosis in patients with invasive breast cancer. Oncol Lett 2016;12(4):260612. [254] Guo D, Song X, Guo T, Gu S, Chang X, Su T, et al. Vimentin acetylation is involved in SIRT5-mediated hepatocellular carcinoma migration. Am J Cancer Res 2018;8(12):245366. [255] Bai L, Lin G, Sun L, Liu Y, Huang X, Cao C, et al. Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway. Oncotarget 2016;7(26):4037786. [256] Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol 2010;11(3):2208. [257] Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature 2001;411(6835):36674. [258] Langsfeld ES, Bodily JM, Laimins LA. The deacetylase sirtuin 1 regulates human papillomavirus replication by modulating histone acetylation and recruitment of DNA damage factors NBS1 and Rad51 to viral genomes. PLoS Pathog 2015;11(9):e1005181.

II. Sirtuins and cancer

150

8. Sirtuins and the hallmarks of cancer

[259] Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 2008;135(5):90718. [260] Dobbin MM, Madabhushi R, Pan L, Chen Y, Kim D, Gao J, et al. SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat Neurosci 2013;16(8):100815. [261] Jeong SM, Haigis MC. Sirtuins in cancer: a balancing act between genome stability and metabolism. Mol Cell 2015;38(9):7508. [262] Mukherjee S, Sinha D, Bhattacharya S, Srinivasan K, Abdisalaam S, Asaithamby A. Werner syndrome protein and DNA replication. Int J Mol Sci 2018;19(11). [263] Das D, Bristol ML, Smith NW, James CD, Wang X, Pichierri P, et al. Werner helicase control of human papillomavirus 16 E1-E2 DNA replication is regulated by SIRT1 deacetylation. mBio 2019;10(2). [264] Lin YH, Yuan J, Pei H, Liu T, Ann DK, Lou Z. KAP1 deacetylation by SIRT1 promotes non-homologous end-joining repair. PLoS One 2015;10(4):e0123935. [265] Yu W, Li L, Wang G, Zhang W, Xu J, Liang A. KU70 inhibition impairs both non-homologous end joining and homologous recombination DNA damage repair through SHP-1 induced dephosphorylation of SIRT1 in T-cell acute lymphoblastic leukemia (T-ALL) [corrected]. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol 2018;49(6):211123. [266] Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol 2003;23(9):317385. [267] Singh CK, Chhabra G, Ndiaye MA, Garcia-Peterson LM, Mack NJ, Ahmad N. The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal 2018;28(8):64361. [268] Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010;17(1):4152. [269] Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol 2008;28(20):6384401. [270] Chang AR, Ferrer CM, Mostoslavsky R. SIRT6, a mammalian deacylase with multitasking abilities. Physiol Rev 2020;100(1):14569. [271] Lombard DB, Schwer B, Alt FW, Mostoslavsky R. SIRT6 in DNA repair, metabolism and ageing. J Intern Med 2008;263(2):12841. [272] Xu Z, Zhang L, Zhang W, Meng D, Zhang H, Jiang Y, et al. SIRT6 rescues the age related decline in base excision repair in a PARP1dependent manner. Cell Cycle 2015;14(2):26976. [273] Hwang BJ, Jin J, Gao Y, Shi G, Madabushi A, Yan A, et al. SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclease, and Rad9-Rad1-Hus1 checkpoint clamp. BMC Mol Biol 2015;16:12. [274] Onn L, Portillo M, Ilic S, Cleitman G, Stein D, Kaluski S, et al. SIRT6 is a DNA double-strand break sensor. eLife 2020;9:126. e51636. Available from: https://doi.org/10.7554/eLife.51636. [275] Vazquez BN, Thackray JK, Serrano L. Sirtuins and DNA damage repair: SIRT7 comes to play. Nucleus 2017;8(2):10715. [276] von Zglinicki T, Saretzki G, Ladhoff J, d’Adda di Fagagna F, Jackson SP. Human cell senescence as a DNA damage response. Mech Ageing Dev 2005;126(1):11117. [277] Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 2008;452(7186):4926. [278] Jung-Hynes B, Ahmad N. SIRT1 controls circadian clock circuitry and promotes cell survival: a connection with age-related neoplasms. FASEB J: Off Publ Federation Am Soc Exp Biol 2009;23(9):28039. [279] Palacios JA, Herranz D, De Bonis ML, Velasco S, Serrano M, Blasco MA. SIRT1 contributes to telomere maintenance and augments global homologous recombination. J Cell Biol 2010;191(7):1299313. [280] Tennen RI, Bua DJ, Wright WE, Chua KF. SIRT6 is required for maintenance of telomere position effect in human cells. Nat Commun 2011;2:433. [281] Chen J, Zhang B, Wong N, Lo AW, To KF, Chan AW, et al. Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth. Cancer Res 2011;71(12):413849. [282] Sasaki T, Maier B, Bartke A, Scrable H. Progressive loss of SIRT1 with cell cycle withdrawal. Aging Cell 2006;5(5):41322. [283] Anwar T, Khosla S, Ramakrishna G. Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status. Cell Cycle 2016;15(14):188397. [284] Son MJ, Kwon Y, Son T, Cho YS. Restoration of mitochondrial NAD(1) levels delays stem cell senescence and facilitates reprogramming of aged somatic cells. Stem Cell 2016;34(12):284051. [285] Yao H, Chung S, Hwang JW, Rajendrasozhan S, Sundar IK, Dean DA, et al. SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J Clin Invest 2012;122(6):203245. [286] Zu Y, Liu L, Lee MY, Xu C, Liang Y, Man RY, et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res 2010;106(8):138493. [287] Kim MY, Kang ES, Ham SA, Hwang JS, Yoo TS, Lee H, et al. The PPARdelta-mediated inhibition of angiotensin II-induced premature senescence in human endothelial cells is SIRT1-dependent. Biochem Pharmacol 2012;84(12):162734. [288] Menghini R, Casagrande V, Cardellini M, Martelli E, Terrinoni A, Amati F, et al. MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation 2009;120(15):152432. [289] Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2006;124(2):31529. [290] Cacchione S, Biroccio A, Rizzo A. Emerging roles of telomeric chromatin alterations in cancer. J Exp Clin Cancer Res: CR 2019;38(1):21. [291] Warburg O. On the origin of cancer cells. Science 1956;123(3191):30914. [292] Guarente L. The many faces of sirtuins: sirtuins and the Warburg effect. Nat Med 2014;20(1):245. [293] Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016;23(1):2747. [294] Zhu S, Dong Z, Ke X, Hou J, Zhao E, Zhang K, et al. The roles of sirtuins family in cell metabolism during tumor development. Semcancer Biol 2019;57:5971. [295] Kim HS, Xiao C, Wang RH, Lahusen T, Xu X, Vassilopoulos A, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab 2010;12(3):22436.

II. Sirtuins and cancer

References

151

[296] Simeoni F, Tasselli L, Tanaka S, Villanova L, Hayashi M, Kubota K, et al. Proteomic analysis of the SIRT6 interactome: novel links to genome maintenance and cellular stress signaling. Sci Rep 2013;3:3085. [297] Ye X, Li M, Hou T, Gao T, Zhu WG, Yang Y. Sirtuins in glucose and lipid metabolism. Oncotarget 2017;8(1):184559. [298] Corbet C, Draoui N, Polet F, Pinto A, Drozak X, Riant O, et al. The SIRT1/HIF2alpha axis drives reductive glutamine metabolism under chronic acidosis and alters tumor response to therapy. Cancer Res 2014;74(19):550719. [299] Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem 2012;287(6):38508. [300] Kleszcz R, Paluszczak J, Baer-Dubowska W. Targeting aberrant cancer metabolism - the role of sirtuins. Pharmacol Rep: PR 2015; 67(6):106880. [301] Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, et al. Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress. EMBO J 2014;33(12):130420. [302] Cha Y, Han MJ, Cha HJ, Zoldan J, Burkart A, Jung JH, et al. Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis. Nat Cell Biol 2017;19(5):44556. [303] Kwon OS, Han MJ, Cha HJ. Suppression of SIRT2 and altered acetylation status of human pluripotent stem cells: possible link to metabolic switch during reprogramming. BMB Rep 2017;50(9):4356. [304] Yang H, Bi Y, Xue L, Wang J, Lu Y, Zhang Z, et al. Multifaceted modulation of SIRT1 in cancer and inflammation. Crit Rev Oncog 2015;20(12):4964. [305] Ozden O, Park SH, Wagner BA, Song HY, Zhu Y, Vassilopoulos A, et al. SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radic Biol Med 2014;76:16372. [306] Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A 2008;105(38):1444752. [307] Cimen H, Han MJ, Yang Y, Tong Q, Koc H, Koc EC. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 2010;49(2):30411. [308] Rahman M, Nirala NK, Singh A, Zhu LJ, Taguchi K, Bamba T, et al. Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase beta and regulates complex V activity. J Cell Biol 2014;206(2):289305. [309] Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010;12(6):6627. [310] Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 2010;40(6):893904. [311] Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010;464(7285):1215. [312] Herrero-Yraola A, Bakhit SM, Franke P, Weise C, Schweiger M, Jorcke D, et al. Regulation of glutamate dehydrogenase by reversible ADP-ribosylation in mitochondria. EMBO J 2001;20(10):240412. [313] Sebastian C, Mostoslavsky R. The role of mammalian sirtuins in cancer metabolism. SemCell Dev Biol 2015;43:3342. [314] Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006;126(5):94154. [315] Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ, Castronovo V, et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem 2007;282(46):3358392. [316] Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 2013;50(5):68698. [317] Laurent G, de Boer VC, Finley LW, Sweeney M, Lu H, Schug TT, et al. SIRT4 represses peroxisome proliferator-activated receptor alpha activity to suppress hepatic fat oxidation. Mol Cell Biol 2013;33(22):455261. [318] Zhou L, Wang F, Sun R, Chen X, Zhang M, Xu Q, et al. SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep 2016;17(6):81122. [319] Tang Z, Li L, Tang Y, Xie D, Wu K, Wei W, et al. CDK2 positively regulates aerobic glycolysis by suppressing SIRT5 in gastric cancer. Cancer Sci 2018;109(8):25908. [320] Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 2013;50(6):91930. [321] Sadhukhan S, Liu X, Ryu D, Nelson OD, Stupinski JA, Li Z, et al. Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc Natl Acad Sci U S A 2016;113(16):43205. [322] Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 2009;137(3):56070. [323] Ogura M, Nakamura Y, Tanaka D, Zhuang X, Fujita Y, Obara A, et al. Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1. Biochem Biophys Res Commun 2010;393(1):738. [324] Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 2014;19(4):60517. [325] Gil R, Barth S, Kanfi Y, Cohen HY. SIRT6 exhibits nucleosome-dependent deacetylase activity. Nucleic Acids Res 2013;41(18):853745. [326] Wu M, Seto E, Zhang J. E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells. Oncotarget 2015;6(13):1125263. [327] Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010;140(2):28093. [328] Lerrer B, Cohen HY. The guardian: metabolic and tumour-suppressive effects of SIRT6. EMBO J 2013;32(1):78. [329] Shin J, He M, Liu Y, Paredes S, Villanova L, Brown K, et al. SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep 2013;5(3):65465. [330] Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001; 410(6825):22730.

II. Sirtuins and cancer

152

8. Sirtuins and the hallmarks of cancer

[331] Villalba JM, Alcain FJ. Sirtuin activators and inhibitors. Biofactors 2012;38(5):34959. [332] Hu J, Jing H, Lin H. Sirtuin inhibitors as anticancer agents. Future Med Chem 2014;6(8):94566. [333] Wang Y, He J, Liao M, Hu M, Li W, Ouyang H, et al. An overview of Sirtuins as potential therapeutic target: structure, function and modulators. Eur J Med Chem 2019;161:4877. [334] Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425(6954):1916. [335] Zhou Z, Ma T, Zhu Q, Xu Y, Zha X. Recent advances in inhibitors of sirtuin1/2: an update and perspective. Future Med Chem 2018;10 (8):90734. [336] Maiese K, Chong ZZ, Shang YC, Wang S. Translating cell survival and cell longevity into treatment strategies with SIRT1. Rom J Morphol Embryol 2011;52(4):117385. [337] Chauhan D, Bandi M, Singh AV, Ray A, Raje N, Richardson P, et al. Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells. Br J Haematol 2011;155(5):58898. [338] Nadal-Serrano M, Pons DG, Sastre-Serra J, Blanquer-Rossello Mdel M, Roca P, Oliver J. Genistein modulates oxidative stress in breast cancer cell lines according to ERalpha/ERbeta ratio: effects on mitochondrial functionality, sirtuins, uncoupling protein 2 and antioxidant enzymes. Int J Biochem Cell Biol 2013;45(9):204551. [339] Zendedel E, Butler AE, Atkin SL, Sahebkar A. Impact of curcumin on sirtuins: a review. J Cell Biochem 2018;119(12):10291300. [340] Yi YW, Kang HJ, Kim HJ, Kong Y, Brown ML, Bae I. Targeting mutant p53 by a SIRT1 activator YK-3-237 inhibits the proliferation of triple-negative breast cancer cells. Oncotarget 2013;4(7):98494. [341] Audrito V, Vaisitti T, Rossi D, Gottardi D, D’Arena G, Laurenti L, et al. Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Res 2011; 71(13):447383. [342] Jung-Hynes B, Nihal M, Zhong W, Ahmad N. Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? The J Biol Chem 2009;284(6):382332. [343] Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D’Silva NJ, et al. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer 2011;117(8):16708. [344] Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 2008;13(5):45463. [345] Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D, et al. Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 2012;119(8):190414. [346] Rotili D, Tarantino D, Nebbioso A, Paolini C, Huidobro C, Lara E, et al. Discovery of salermide-related sirtuin inhibitors: binding mode studies and antiproliferative effects in cancer cells including cancer stem cells. J Med Chem 2012;55(24):1093747. [347] Lara E, Mai A, Calvanese V, Altucci L, Lopez-Nieva P, Martinez-Chantar ML, et al. Salermide, a Sirtuin inhibitor with a strong cancerspecific proapoptotic effect. Oncogene 2009;28(6):78191. [348] Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, et al. Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene 2006;25(2):17685. [349] Kojima K, Ohhashi R, Fujita Y, Hamada N, Akao Y, Nozawa Y, et al. A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells. Biochem. Biophys Res Commun 2008;373(3):4238. [350] Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S, et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res 2006;66(8):436877. [351] Marshall GM, Liu PY, Gherardi S, Scarlett CJ, Bedalov A, Xu N, et al. SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS Genet 2011;7(6):e1002135.

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9 The bifunctional roles of sirtuins and their therapeutic potential in cancer Yeuan Ting Lee*, Yi Jer Tan*, Pei Yi Mok, Ayappa V. Subramaniam and Chern Ein Oon Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia O U T L I N E 9.1 The mammalian sirtuins 9.1.1 SIRT1 9.1.2 SIRT2 9.1.3 SIRT3 9.1.4 SIRT4 9.1.5 SIRT5 9.1.6 SIRT6 9.1.7 SIRT7

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9.1 The mammalian sirtuins Sirtuins (SIRTs) are highly conserved class III histone deacetylases that utilize NAD1 as a cofactor to sense energy fluctuations resulting from oxidative, metabolic, or genotoxic stress followed by the coordination of appropriate responses [1,2]. The enzymatic activities of SIRTs are lysine deacetylase and/or mono-ADP-ribosyltransferase that targets both histone and nonhistone proteins [3,4]. The seven members of the mammalian SIRT family (SIRT17) have varied specificity, catalytic activity, localization, and substrates; and share a catalytic domain of B275 amino acids with variable lengths of unique additional N-terminal and/or C-terminal sequences [3,5]. Furthermore, mammalian SIRTs differ in subcellular localizations: SIRT1 is prominently present in the nucleus but also found in the cytosol; SIRT2 in the cytoplasm; SIRT35 mainly mitochondrial; SIRT6 in the nucleus; and SIRT7 in the nucleolus [1,5]. Generally, SIRT functions can be classified into four main processes: chromatin regulation, cell survival under stress, metabolic homeostasis regulation, and developmental and cell differentiation [6]. SIRTs are highly conserved enzymes implicated in many biological processes linked to longevity, aging, DNA repair, epigenetic regulation, and metabolism homeostasis. Dysregulation of either one of these processes could result in tumorigenesis [2,79]. Increasing evidence has demonstrated the crucial role of SIRTs in cancer initiation and progression, and thus SIRTs have become the focus of increasing attention as potential targets in anticancer therapy [3,6,911]. However, various reports have highlighted SIRTs to possess bifunctional and contradicting roles in cancer. In the event of cellular stress, the opposed roles of SIRTs can be exhibited, for instance, via the maintenance of DNA integrity (antitumor) versus promotion of cell survival under stress (protumor) (Fig. 9.1). This chapter will discuss the roles of mammalian SIRTs in tumorigenesis and the development of SIRT modulators as anticancer agents. * These authors contributed equally to this work and are joint first authors.

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FIGURE 9.1 Dual role and function of sirtuins in cancer.

9.1.1 SIRT1 SIRT1 is a deacetylase targeting a variety of substrates involved in the modulation of cancer cell proliferation, survival, and apoptosis. SIRT1 levels were found to be dysregulated and overexpressed in many types of cancer, including breast, colon, lung, liver, pancreatic, prostate, leukemia and lymphoma, ovarian, and cervical cancers [12]. SIRT1 has been linked to tumor-suppressive or tumor-promoting roles in cancer, through the targeting of diverse signaling pathways, depending on the cancer type and cellular context. 9.1.1.1 SIRT1 as a tumor suppressor SIRT1 is an important chromatin regulator that is necessary for the maintenance of genome stability and repair of damaged DNA [13,14]. Events of DNA damage such as double-stranded breakage (DSBs) are repaired by homologous recombination (HR) or nonhomologous end-joining (NHEJ) modulated by SIRT1 [15,16]. Recent studies have revealed that SIRT1-deficient cells are more susceptible to chromosomal aberrations and fusions upon DNA damage, which is indicative of an impaired DNA repair mechanism [13]. Interestingly, the degree of SIRT1 expression was found to negatively correlate with skin cancer progression, mainly through the deacetylation of skin pigment xeroderma pigmentosum C (XPC) protein which is essential for the initiation of global genome nucleotide excision repair (NER). Furthermore, high SIRT1 activity was reported to reduce the tumorigenesis of liver cancer in vivo by protecting liver tissues from metabolic and DNA damage [14,17]. Low SIRT1 levels were also found to correlate with BRCA1 mutations in breast cancer [18]. In addition, SIRT1 possesses inhibitory roles in cancer cell growth through the modulation of signaling pathways and deacetylation of several targets [1921]. The effect of varied SIRT1 levels on similar targets may yield contradictory responses and result in different outcomes due to the contrasting roles of numerous SIRT1 targets. In the context of cancer suppression, the moderate increase in SIRT1 levels has been shown to reduce spontaneous carcinomas, sarcomas, and the incidence of tumorigenesis in APC1/min mice [17,22]. SIRT1 also deacetylates HIF-1α and blocks the transcription of downstream genes to subsequently impede tumor growth and angiogenesis in vivo [19]. Moreover, activated SIRT1 is capable of deacetylating the c-MYC protein for degradation in a negative feedback loop and results in the blockade of cervical cancer cell proliferation [21,23]. SIRT1 is the regulator of the forkhead O family (FOXO) transcription factors that are crucial for cell proliferation, differentiation, and survival, which are all implicated in tumorigenesis [2427]. SIRT1-mediated activation of FOXO3a was found to induce cell cycle arrest and oxidative stress resistance but inhibits FOXO3a-induced cell death, highlighting the partial antitumor role of SIRT1 [28]. Next, SIRT1 can promote autophagosome maturation for the removal of cellular waste and substances harboring malfunctions and mutations through autophagy [29]. The depletion of SIRT1 was found to associate with and may promote the development of prostatic intraepithelial neoplasia (PIN) [30]. The Wnt/β-catenin signaling pathway which is constitutively expressed in many cancer types, is critical for cell differentiation, embryo developments, as well as tumorigenesis [3134]. SIRT1 was found to deacetylate and block cytoplasmic-to-nuclear translocation of β-catenin which impeded cell proliferation and tumorigenesis in pancreatic cancer cells and colon cells, respectively

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[35,36]. NF-κB plays a central role in the regulation of immune responses and inflammation, such that its dysregulation can lead to tumorigenesis [37,38]. NF-κB is a target of SIRT1 deacetylase activity, and the removal of acetylated NF-κB subunits can result in the suppression of downstream transcriptional activity leading to an inhibition of its prosurvival function [39,40]. A decrease in SIRT1 activity as a result of cigarette smoke exposure, can induce NF-κB acetylation at the RelA/p65 proinflammatory mediator, which is a precursor of non-small cell lung carcinoma [41,42]. As higher SIRT1 levels were linked to the recurrence-free survival rate of prostate cancer patients, in vivo studies revealed that the increased SIRT1 level may be due to the reaction to cancer rather than the cause of tumorigenesis [43]. 9.1.1.2 SIRT1 as an oncoprotein Conversely, SIRT1 has been identified to promote cancer cell survival and tumor progression, given that SIRT1deleted APC1/min mice showed an increase in tumor apoptosis [44]. The knockdown of SIRT1 was also observed to inhibit the expression of HIF-1α downstream target genes in mice harboring hepatocellular carcinoma (HCC) [45]. In addition, one study reported that deacetylation of c-MYC by SIRT1 could reinforce its stability for NAD1 synthesis which could, in turn, enhance tumorigenesis [46]. In prostate cancer, inhibition of SIRT1 resulted in lower cell viability, cell growth, and chemoresistance which provided insights into the oncogenic roles of SIRT1 [47]. However, the oncogenic function of SIRT1 may require additional factors given that the overexpression of SIRT1 alone did not increase tumor formation in vivo [43]. SIRT1 can display oncogenic properties through crippling the functions of several tumor suppressors such as p53, p73, and HIC1 proteins [48]. One possible oncogenic role of SIRT1 is through the suppression of p53 and p300 (histone acetyltransferase of p53) activities via deacetylation of these substrates [49,50]. As p53 modulates cell fate such as DNA repair, cell cycle arrest, and apoptosis, p53 deacetylation by SIRT1 could reduce p53-mediated apoptosis and hamper p53-induced cellular senescence [51,52]. The TGF-β signaling pathway is involved in cell growth, differentiation, migration, apoptosis, and other key physiological and pathological processes [53,54]. SIRT1 has been demonstrated to regulate TGF-β through deacetylating Smad7 leading to its ubiquitination, which subsequently inhibits TGF-β-dependent apoptosis [55]. One factor that could have contributed to the contradictory roles of SIRT1 is the subcellular localization in different cell lines. Both SIRT1 and p53 contain nuclear localization signals and nuclear export signals which facilitate the shuttling of both types of proteins through the nuclear envelope under different circumstances [56,57]. For instance, some cancers such as prostate, lung, breast, and skin cancer showed mainly cytoplasmic expressions of SIRT1 and nuclear p53 compared to normal tissues which are both found localized primarily in the nucleus [58,59]. The difference in localization allows for a reduced interaction between SIRT1 and p53, thus minimizing the regulation on p53 transcription. Therefore the tumorpromoting or suppressing properties of SIRT1, in this case, depended on other SIRT1 targets present in the cytoplasm. The difference in the cellular localization of SIRT1 in different cancer types could explain why SIRT1 can act as a tumor suppressor in some, but as an oncoprotein in others. Another factor that could contribute to the contrasting effect of SIRT1 in cancer is the mutation profile of SIRT1-targeted proteins. Several studies have reported the antitumor role of SIRT1 in cells with nonfunctional p53 in vivo and displayed oncogenic behavior in PTENdeficient prostate cancer mice models [60,61]. Furthermore, the role of SIRT1 in tumorigenesis may be agedependent, probably due to an accumulation of mutations of SIRT1 regulators and targets [62].

9.1.2 SIRT2 SIRT2 is a deacetylase that is involved in the regulation of chromatin assembly, promotion of chromosomal stability, and control of the cell cycle during early metaphase checkpoint regulation; involving the deacetylation of α-tubulin and interaction with histone methyltransferase PR-Set7 [6366]. SIRT2 is also involved in the regulation of mitotic processes, cell motility, differentiation, oxidative metabolism, and cell death [63]. The role of SIRT2 is tumor-specific and dependent on cellular context. Generally, SIRT2 deacetylates various substrates involved in the modulation of the cell cycle, which include H4K16, p53, p65, FOXO1, FOXO3, and CDK4 [67]. SIRT2 has bifunctional roles in cancer. SIRT2 has been shown to inhibit cancer cell growth through deacetylating β-catenin and KDM4A [68,69], but increase cell proliferation and decrease the overall survival of patients with pancreatic cancer, HCC, or neuroblastoma [7072]. In addition, SIRT2 can also play contrasting roles in tumors of different grades and classifications. Low SIRT2 expression in moderately differentiated grade 2 breast tumors contributed to impaired cell cycle and poor prognosis. Conversely, the high SIRT2 levels in poorly differentiated grade 3 breast tumors are responsible for more aggressive tumors, a lower relapse-free period, and mortality contributed by cell cycle dysregulation and crippled DNA repair mechanism [73].

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9.1.2.1 SIRT2 as a tumor suppressor SIRT2 is downregulated and depleted in several types of cancers including breast cancer, glioma, HCC, neck squamous cell carcinoma, non-small cell lung cancer (NSCLC), and prostate cancer [63,7377]. The low expression of SIRT2 was linked to cancer progression and promotion of cancer cell migration, invasion, and metastasis [78]. SIRT2 exhibits antitumor properties mainly through deacetylating key proteins involved in cell proliferation, cell integrity, and DNA damage pathways [72]. SIRT2 also acts to maintain proper cell cycle checkpoint and chromatin regulation to prevent the formation of hyperploid cells. A study by Kim and colleagues found that SIRT2-deficient mice developed liver, intestinal, and mammary tumors as a result of cell cycle disruption [76]. Moreover, SIRT2 was reported to suppress skin cancer in vivo, and reduced SIRT2 expression was observed in both breast and liver cancer tissues from clinical samples [66,79]. Furthermore, SIRT2 can induce apoptosis in the event of DNA damage either via deacetylating p53 and repressing p53-mediated transcriptional activation or through deacetylating FOXO3a, and triggers caspase-dependent apoptosis in breast cancer and kidney cells [80,81]. 9.1.2.2 SIRT2 as an oncoprotein SIRT2 is overexpressed in some cancers such as neuroblastomas and pancreatic cancer cells; while knockdown of SIRT2 resulted in apoptosis of glioma and cervical cancer cell lines [12]. SIRT2 is also highly expressed and responsible for cell proliferation, invasion, and tumor growth in leukemia, neuroblastoma, HCC, and pancreatic cancer. SIRT2 is known to inhibit p53 such that the diminishment of SIRT2 activity was shown to reduce p53 acetylation and activate apoptosis in cancer cell lines. In addition, SIRT2 overexpression has been shown to cause MYC activation, which subsequently increased antioxidant production and inhibited apoptosis in cholangiocarcinoma [82]. SIRT2 activity was shown to promote cell proliferation via increasing N-MYC and c-MYC protein stability in neuroblastomas and pancreatic cells respectively [71]. Furthermore, SIRT2 was reported to positively regulate epithelialmesenchymal transition (EMT) by reducing E-cadherin expression, leading to increased cancer cell migration and invasion in vivo [68]. The deacetylation of protein kinase B (AKT) by SIRT2 will also result in the activation and enhancement of EMT through the RAS/ERK/JNK/MMP-9 pathway and the AKT/GSK3β/β-catenin signaling pathway. Subsequently, this has been shown to promote the migration and invasion of gastric cancer and HCC, respectively [77,83]. A study by Jing and colleagues reported that SIRT2 inhibition resulted in MYC reduction through ubiquitination and degradation in vitro and in vivo, which is required for the growth and survival of transformed breast cancer cells [84]. Interestingly, tumors expressing high levels of SIRT2 were found to possess enhanced tumorigenesis and exhibit enhanced resistance to chemotherapy due to the deacetylation of KRAS (a SIRT2 substrate) leading to its activation [85].

9.1.3 SIRT3 SIRT3 is a NAD1-dependent deacetylase that is mainly localized in the mitochondria [86]. The full-length SIRT3 protein (44 kDa) is inactive, and proteolytic cleavage is required for the release of the active enzyme (28 kDa) [87]. SIRT3 regulates intracellular processes which include metabolism, longevity, aging, cancer, and stress responses [88]. The function of SIRT3 may be different depending on the cell-type and tumor-type; thereby, SIRT3 may act as an oncogene or a tumor suppressor. High SIRT3 expression was observed in various cancer types, such as NSCLC, breast cancer, oral squamous cell carcinoma (OSCC), renal cancer, colon cancer, gastric cancer, melanoma, and esophageal cancer [69,8995]. On the other hand, low level of SIRT3 was also reported in different cancer types including hepatocellular cancer, pancreatic cancer, osteosarcoma, prostate, ovarian cancer, B-cells malignancies, and breast cancer [9698]. 9.1.3.1 SIRT3 as a tumor suppressor Among all types of cancers, a total of 20% of cancer types consisted of deleted SIRT3 gene [99]. Moreover, in testicular, prostate, and hepatocellular tumors, the gene expression level of SIRT3 was found to be lower in cancer cells relative to normal cells [98,99]. SIRT3 protein levels were also found to be lower in human breast tumors compared to normal tissues, and mice lacking SIRT3 were more susceptible to mammary cancer [98100]. The lack of SIRT3 can lead to poor prognosis and result in low patient survival rate [100]. Compared to SIRT1 and SIRT2, SIRT3 is a highly context-specific tumor suppressor. The major tumor suppression function of SIRT3 is repressing ROS-mediated damage which may otherwise cause DNA mutations, genomic instability, and activation of metabolism, cell survival, and proliferation pathways, leading to tumorigenesis [101]. One of the functions of SIRT3 is to promote the regeneration of antioxidant glutathione via deacetylating and activating both mitochondrial manganese superoxide dismutase (MnSOD2) and isocitrate dehydrogenase 2 (IDH2) [102104].

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In addition, SIRT3 activates mitochondrial respiration via the pyruvate dehydrogenase complex (PDC) which is usually inactivated in cancer cells [105107]. The mitochondria play central roles in the production of ROS with a tightly controlled threshold [108]. High ROS levels may cause damage in DNA, proteins, and lipids, which can result in mitochondrial dysfunction and carcinogenesis [109]. One major function of SIRT3 is to prevent oxidative damage by limiting ROS production through the regulation of MnSOD and IDH activities [98,109]. MnSOD is involved in superoxide (O2 2 ) detoxification via the conversion of superoxide to hydrogen peroxide, and then to water [110,111]. On the other hand, IDH is responsible for converting isocitrate to α-ketoglutarate for the production of nicotinamide adenine dinucleotide phosphate (NADPH) [103]. In the event of oxidative stress, SIRT3 deacetylates and activates FoxO3a to promote the transcription of oxidative stress response genes (such as SOD2, IDH, and catalase) to reduce the level of ROS [112]. SIRT3-knockout have resulted in increased ROS in vitro and in vivo. The unregulated high levels of ROS may cause genomic, metabolic, and microenvironmental-associated instabilities, leading to enhanced cancer survival and induced therapeutic resistance [98,108,111]. The loss of SIRT3 appears to drive HIF activation and enhance the hypoxia-inducible factor-1 (HIF) response to hypoxia through a ROS-dependent mechanism, such that the upregulation of HIF activity is strongly associated with cancer cell survival and proliferation [98,99]. A study by Kim and colleagues demonstrated that SIRT3-deficient cells can cause invasive and tumorigenic phenotypes in vitro and in vivo; mainly through the expression of MYC and RAS oncogenes which resulted in increased chromosomal aberrations and tumor growth in athymic nude mice [98]. The downregulation of SIRT3 in breast cancer was reported to promote cancer glycolysis and cell proliferation [97]. Moreover, SIRT3 was reported to play proapoptotic roles in colorectal cancer (CRC) and HCC cells through the JNK and GSK-3β/Bax signaling pathways, respectively [113,114]. SIRT3 was also shown to downregulate glutathione S-transferase P1 (GSTP1), activate the JNK and c-Jun pathway, and upregulate the proapoptotic Bim protein to sensitize HCC cells to chemotherapeutic agents [115]. 9.1.3.2 SIRT3 as an oncoprotein The overexpression of SIRT3 in cancer, such as glioma, was shown to inhibit apoptosis, disrupt cell cycle, and promote CpG island hypermethylation [116]. SIRT3 is also elevated in breast and OSCC cancer cells, and reportedly inhibited p53-induced growth arrest in human bladder cancer cells [95,117,118]. In addition, SIRT3knockdown was reported to inhibit the proliferation and sensitize OSCC cells to radiation and chemotherapy treatments in vivo [95]. High SIRT3 expression is positively correlated with tumor progression, poor prognosis, and low patient survival [94,96]. Overexpression of SIRT3 was found to promote cell proliferation and enhance ATP generation, glucose uptake, glycogen formation, increased MnSOD activity, and lactate production, as well as inducing an aggressive phenotype in gastric cancer cells [69]. Silencing of SIRT3 led to the inhibition of cancer cell growth, proliferation, invasion, migration, and sensitized cancer cells to chemotherapy and radiation [90,92]. SIRT3 knockdown also reduced cell proliferation, colony formation, and migration, as well as induced senescence and G1-phase arrest in human melanoma cells [93]. Furthermore, SIRT3 was described to deacetylate histone proteins H4K16Ac and H3K9Ac which could lead to genomic instability. H4K16Ac is linked to the regulation of cell cycle progression, transcription, DNA repair, and DNA replication; deacetylation of H3K9Ac is required for H3K9me2/3 methylation [4]. SIRT3 also deacetylates human 8-oxoguanine-DNA glycosylase 1 (OGG1) which is a base excision repair (BER) enzyme to prevent degradation and limit apoptotic death in cells subjected to oxidative stress. Cheng and colleagues reported that the loss of SIRT3 led to increasing acetylation and degradation of OGG1 which can promote stress-induced apoptosis in glioblastoma cancer cells [119]. SIRT3 was reported to deacetylate tumor suppressor p53 and partially abrogate p53 activity, to promote cancer cell proliferation, and enact cellular growth arrest and senescence in human bladder cancer cells [117]. SIRT3 also inhibits mitochondrial translocation of pro-apoptotic protein Bax for the maintenance of mitochondrial membrane integrity.

9.1.4 SIRT4 SIRT4 is present primarily in the mitochondrial matrix and is involved in various mitochondrial metabolic processes. Unlike the other SIRTs, SIRT4 was initially known to be ADP-ribosyltransferase but lacked NAD1-dependent deacetylase activity [120,121]. However, in a recent study, SIRT4 was reported to exhibit lysine deacetylase activity. SIRT4 is involved mainly in regulation of cell metabolism. SIRT4 was found to regulate the leucine metabolism and insulin secretion to maintain the glucose homeostasis in the cells [122]. In lipid metabolism, SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), which is involved in fatty acid oxidation, as well as functions as lipoamidase [123,124].

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9.1.4.1 SIRT4 as a tumor suppressor Reduced SIRT4 mRNA levels have been correlated with poor prognosis in colorectal, bladder, breast, lung, esophagus, and gastric cancers [125129]. SIRT4 was reported to regulate glutamine metabolism which is a key player in cancer cell growth and proliferation [130]. Under normal conditions, SIRT4 suppresses tumor growth via ADP-ribosylation and inhibition of glutamate dehydrogenase (GDH) [121,131]. GDH is a mitochondrial enzyme that converts glutamate into α-ketoglutarate in the tricarboxylic acid (TCA) cycle, which is a series of ATP-synthesis metabolic reactions. SIRT4 downregulates GDH activity via ADP-ribosylation, resulting in reduced insulin secretion which negatively affects energy supply. A study conducted by Jeong and colleagues demonstrated that overexpression of SIRT4 significantly inhibited the proliferation of Burkitt lymphoma cells via repression of the mitochondrial glutamine metabolism [132,133]. Moreover, SIRT4 has been linked to the maintenance of genomic stability and cancer initiation. The loss of SIRT4 could lead to both increased glutaminedependent proliferation and stress-induced genomic instability which can promote tumorigenesis in lung cancer, as evident in SIRT4 knockout mice [132]. This study also reported that SIRT4 may inhibit glutamine utilization upon DNA damage and results in cell cycle arrest. The mitochondrial regulator proteins including mitofusins, optic atrophy protein 1 (OPA1), and dynamin-related proteins (DRPs) are responsible for mitochondrial fusion and fission that promote cancer cell invasion and migration. Overexpression of SIRT4 has been found to deregulate DRP1 via an extracellular signal-regulated protein kinase (ERK) activity, resulting in the reduction of mitochondrial fission in NSCLC [134,135]. The overexpression of SIRT4 was also reported to negatively regulate CRC invasion and metastasis through increase of E-cadherin protein expressions resulting in blockade of EMT [129]. 9.1.4.2 SIRT4 as an oncoprotein Mounting evidence has revealed SIRT4 to exhibit oncogenic properties upon prolonged endoplasmic reticulum (ER) stress and DNA damage, specifically after exposure to chemotherapeutic drugs and ultraviolet light [136,137]. Jeong et al. reported that SIRT4 is capable of protecting cancerous cells against these stresses by inhibiting apoptosis and promoting liver cancer cell survival [137]. The upregulation of SIRT4 expression in liver cancer cells was shown to reduce caspase-3 protein expression and resulted in increased cancer cell survival and growth [137]. SIRT4 overexpression was also found to positively affect breast cancer cell proliferation, migration, and invasion [136]. As such, tumor cells may have utilized SIRT4 as a tool to hijack cellular stress response pathways upon oncogenic stress to increase their growth and survival. The limitations of currently available data on the roles of SIRT4 as an oncogene demonstrate the need for future research.

9.1.5 SIRT5 SIRT5 is a strong lysine desuccinylase, demalonylase, and deglutarylase but a weak deacetylase. SIRT5 is localized in the mitochondria. It targets the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS-1) involved primarily in maintenance of the cellular ammonia homeostasis [138]. The activation of CPS-1 via the removal of glutaryl and succinyl moieties by SIRT5 catalyzes the detoxification of ammonia, which otherwise could induce oxidative stress and subsequently damage the host tissues and drive tumorigenesis [139,140]. In addition, SIRT5 is also involved in the regulation of glycolysis by activating the glyceraldehyde 3-phosphate dehydrogenase (GADPH) activity via demalonylation of a key residue, K184 located on the enzyme’s homodimerization interface, thereby enhancing glycolytic flux in primary hepatocytes [141]. 9.1.5.1 SIRT5 as a tumor suppressor SIRT5 has been reported to regulate cellular ROS levels by desuccinylating Cu/Zn superoxide dismutases (SODs). Recent studies have revealed that binding of SIRT5 to SOD1 could initiate the reduction of ROS level to hamper H1299 lung cancer cell proliferation [142]. In addition, upregulation of SIRT5 was found to correlate with decreased ACOX1, an enzyme involved in acyl-coA catalysis which produces hydrogen peroxide (H2O2) as a byproduct. The desuccinylation activity of SIRT5 on ACOX1 was shown to reduce H2O2 and oxidative stress levels in HCC cells, thus preventing DNA damage and suppressing tumor development [143]. The suppression of HCC development and progression may also be attributed to the negative modulation of EMT [144]. For example, SIRT5 was found to negatively interact with SNAIL and deacetylates vimentin to reduce EMT and consequently inhibit HCC cell migration and metastasis [144]. In tumorigenesis, SNAIL plays vital roles in maintaining cancer stem-like properties to increase replicative ability and drive drug resistance [145,146]. The increase in SIRT5 levels may inhibit SNAIL gene expression which subsequently suppresses metastasis. II. Sirtuins and cancer

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9.1.5.2 SIRT5 as an oncoprotein Elevated SIRT5 mRNA expression in colon, lung, breast, ovarian, melanoma, and pancreas relative to the corresponding normal tissue type suggested its role as a tumor promoter [147]. Overexpression of SIRT5 protein has been reported to be positively linked to larger tumor size, increased lymph node metastasis, and advanced colorectal tumor stage through glutamine metabolic rewiring [148]. SIRT5 can activate glutamate dehydrogenase 1 (GLUD1) to provide an adequate supply of energy to the CRC cells, leading to enhanced cell proliferation and survival. In contrast, when SIRT5 gene expression is silenced, the formation of α-ketoglutarate is inhibited and thereby prevents the entry of glutamine-derived metabolites into the TCA cycle. This will, in turn, suppress the proliferation of CRC cells via increased apoptosis and cell cycle arrest [148]. Overexpression of SIRT5 has been reported to facilitate drug resistance in NSCLC and ovarian cancer [149,150]. Both in vitro and in vivo studies have shown the overexpression of SIRT5 to promote cell proliferation and colony formation, whereas the opposite effect was observed in SIRT5 knockdown cells. The NSCLC cancer cells with depleted SIRT5 are more susceptible to the anticancer drugs, including cisplatin (CDDP), 5-fluorouracil (5-FU), and bleomycin [149]. In addition, SIRT5 has been shown to inhibit ROS-mediated DNA damage and apoptosis upon cisplatin treatment by activating the Nrf2/HO-1 pathway which controls the expression of antioxidant-responses and drug resistance genes in NSCLC cancer cells [149,150]. The deacetylation of FOXO3a and deactivation of BCL-XL by SIRT5 prevent cells from suicide via apoptosis [147,150]. The percentage of apoptosis cells was increased in HCC cells upon SIRT5 knockdown, in correspondence to the upregulation of proapoptotic proteins (i.e., cl-cas3, cl-PARP, and Bax) and downregulation of apoptosis suppressor Bcl-2 [151].

9.1.6 SIRT6 SIRT6, a Sir2 homolog, is a chromatin-bound sirtuin and located primarily in the nucleus. SIRT6 plays a vital role in cancer pathways as SIRT6 mostly functions in the regulation of metabolic homeostasis and DNA repairs [152]. SIRT6 was found to act as mono-ADP-ribosyltransferase [153] and therefore was involved in mono-ADP-ribosylation (MARylation) of PARP1 in DNA repair [154]. During DNA repair, SIRT6 is relocalized to the site of DNA damage, in order to conduct base excision and double-stranded repair by activating the ADP-ribosyltransferase diphtheria toxin-like (ARTD1) enzyme through MARylation [155]. Recently, SIRT6 was found to exhibit histone deacetylase activity on two substrates, H3K9Ac and H3K56Ac, which is essential to promote chromatin modification and support genomic stability. 9.1.6.1 SIRT6 as tumor suppressor A role of SIRT6 has been found in pancreatic ductal adenocarcinoma (PDAC) [156]. The loss of SIRT6 in PDAC can activate the Lin28 oncogene promoter to increase the rate of PDAC progression and metastasis. In contrast, the activation of SIRT6 reduces the hyperacetylation of H3K9Ac and H3K56Ac at the Lin28b promoter region, thereby inhibiting the cellular proliferation and tumor progression [157]. Colon cancer patients harbouring lower levels of SIRT6 protein have a significantly shorter overall survival or disease-free survival time [158]. In CRC, P13K/Akt signaling is an important intracellular pathway in regulating nutrient uptake, cell proliferation, migration, and apoptosis [159]. The inhibition Akt protein upon BKM120 P13K-inhibitor treatment resulted in the dephosphorylation of FOXO3a, to promote apoptosis in colon cancer cells [158]. The loss of SIRT6 expression in CRC cells suppressed the BKM120-induced cell apoptosis by inhibiting the cyto-c release and caspase-9/3 activity. This correlates with the increased cell viability and survival rate among SIRT6-knockdown cells, highlighting the significance of SIRT6 in governing cell death. Besides, the overexpression of SIRT6 protein could inhibit H3K9 acetylation and hamper the protein expression of survivin, thereby causing the cells to undergo apoptosis. In another study, Lin and coworkers have discovered the positive relationship between ubiquitinspecific peptidase (USP10) and SIRT6 in colon cancer. Reduced expression of both USP10 and SIRT6 have been observed in colon cancer cells [160,161]. USP10 works as a deubiquitinase for SIRT6 to protect it from degradation due to ubiquitination in human colon cancer cells. USP10 interacts closely with SIRT6 to inhibit the activation of c-Myc, an oncogene involved in colon cancer cell cycle progression and tumor development. Knockdown of both USP10 and SIRT6 resulted in cell cycle arrest at the S and G2/M phases. 9.1.6.2 SIRT6 as an oncoprotein SIRT6 has been shown to govern cell proliferation and apoptosis in HCC by activating the ERK1/2 signaling pathway [162]. The upregulation of SIRT6 protein expression is positively correlated with the expression of transforming growth factor (TGF)-β1 and H2O2/HOCl ROS to promote anoikis resistance and enhanced tumorigenesis in HCC [163]. In contrast, inhibition of SIRT6 expression will lead to cellular senescence, resulting in the suppression in HCC cell tumorigenicity. The overexpression of SIRT6 also enhanced the invasiveness and migratory ability II. Sirtuins and cancer

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of NSCLC cells via the ERK1/2/MMP9 signaling pathway [164]. In a human skin squamous cell carcinoma (SCC) mice model, a reduction of tumor growth was reported in the SIRT6 skin-specific conditional knockout (cKO) group compared to the wild-type group post treatment with UVB, DMBA, and TPA. In another study, SIRT6 was found to increase cell proliferation and survival through positive regulation of cyclooxygenase-2 (COX-2) expression in skin cancer cells [165].

9.1.7 SIRT7 SIRT7 is the least studied among the SIRT family members. SIRT7 is associated with RNA polymerase I (Pol I) transcriptional machinery, which plays a role in regulating rRNA expression. Although it presents predominantly in the nucleolus, SIRT7 exhibits a weak deacetylase activity compared to SIRT1 and SIRT6. Its role in modulating cellular stressors (ER, mitochondrial, and oxidative stress) to aid cell survival is well documented as a tumor suppressor [166170]. SIRT7 is also involved in DNA damage repair and maintaining genomic stability via the regulation of the p53 tumor suppressor [171]. 9.1.7.1 SIRT7 as a tumor suppressor In pancreatic, breast, and oral cancer patients, the low expression of SIRT7 is positively correlated with increased tumor aggressiveness and reduced survival [172174]. In a well-designed study by McGlynn and colleagues, the survival analysis showed that pancreatic cancer patients with low SIRT7 protein expression have a shorter diseasefree and disease-specific time, suggesting high SIRT7 protein expression could prolong patient survival and tumor recurrence [174]. The downregulation of SIRT7 protein resulted in breast cancer metastasis through the activation of the TGF-β1 signaling pathway, leading to enhanced EMT [172]. In contrast, the overexpression of SIRT7 blocked TGF-β1 signaling and therefore inhibited the EMT process and metastasis in breast cancer. In OSCC, the overexpression of SIRT7 promoted Smad4 deacetylation, which significantly reduced the expression of N-cadherin, vimentin, and MMP7, but increased expression of E-cadherin, indicating the suppression of EMT [173]. 9.1.7.2 SIRT7 as an oncoprotein The H3K18Ac histone is a novel substrate for SIRT7 [175]. The hypoacetylation of H3K18Ac is related to poor prognosis and an aggressive form of pancreatic adenocarcinoma [176,177]. SIRT7 is important to maintain cancer cell phenotypes. The downregulation of SIRT7 in fibrosarcoma cell lines led to impairment of anchorageindependent cellular growth. The SIRT7 knockdown of U251 xenografts study of human glioblastoma revealed disruption to the tumor development, suggesting the protumorigenesis roles of SIRT7 in maintaining cancer development. In another study, SIRT7 protein expression is associated with the metastatic phenotypes of epithelial and mesenchymal tumors [178]. The loss of SIRT7 reduced the migratory ability and invasiveness of the PC3 prostate cancer cell line. The metastatic properties of PC3 cells were linked to the declined expression level of E-cadherin (CDH-1) protein [179]. This indicates that SIRT1 could act as a scaffold protein to recruit SIRT7 in which the latter may suppress the E-cadherin protein expression via H3K18Ac deacetylation. In contrast, there is little effect of SIRT1 activity on E-cadherin repression [178]. SIRT7 is reported to be overexpressed in several cancers, including colon, ovarian, and liver cancers [171,180,181]. Yu and colleagues reported that the overexpression of SIRT7 protein was found to positively linked to the aggressive form of CRC, resulting in a reduced survival rate among patients [182]. SIRT7 overexpression has been demonstrated to promote CRC cell proliferation by increasing ERK1/2 phosphorylation and cyclin D1 protein expression via the activation of the RAS-RAF-MEK-ERK pathway. The study demonstrated the role of SIRT7 in the promotion of cell migration and tumor metastasis via EMT induction in vitro and in vivo. On the other hand, downregulation of SIRT7 significantly inhibited cell growth, proliferation, invasiveness, and migratory ability of CRC cells [182].

9.2 Sirtuin modulators In the previous part, we have discussed the dual roles of each SIRTs in tumor progression. Different tumor type and tumor microenvironments can induce different responses to SIRT regulation. A wide range of sirtuin inhibitors (SIRTi) and sirtuin-activating compounds (STACs) have been discovered and developed (Figs. 9.2 and 9.3). In the following section, different classes of SIRTi and STACs and their effects on the progression of various cancers will be discussed.

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161 FIGURE 9.2 Different classes of sirtuin inhibitors with their relative chemical structures.

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FIGURE 9.3 Structures of cancer-related sirtuin-activating compounds.

9.2.1 Sirtuin inhibitors Increasing evidence indicates that inhibiting SIRTs may interrupt cancer cell biology and tumor progression. Compared to SIRT activators, SIRTi have been widely studied in anticancer research. Many SIRTi have been developed and are available in the market (Table 9.1). SIRTi can be classified into two categories: general SIRTis targeting the NAD1 pocket (e.g., Nicotinamide) and SIRT isotype-specific inhibitors (e.g., EX527, AGK2, sirtinol, cambinol, and tenovins) [11]. These SIRTis have been reported to exert anticancer properties in various cancer types. Below is the summary of different classes of SIRTi with their roles in inhibiting tumor progression. 9.2.1.1 Nicotinamide and its analogues Nicotinamide (NAM) is a form of vitamin B3 (nicotinic acid) that provides NAD1 as a substrate to non-redox enzymes including the SIRTs family proteins [198]. NAM maintains the NAD1 redox homeostasis and could modulate SIRT activity through noncompetitive product inhibition mechanisms and regenerating NAD in salvage pathways [199]. In brief, NAM is the by-product generated by SIRTs and is an endogenous inhibitor of the SIRTs deacetylation activity [200]. NAM is cleaved by nicotinamidase (Pnc1), to maintain a low level of NAM. NAM is a well-known water-soluble SIRTi shown to exhibit an inhibitory effect toward SIRT1 in vitro [198,200].

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TABLE 9.1 Commercial SIRTi used in anticancer research. Sirtuin inhibitor

Target

IC50 (cell free assay)

References

Nicotinamide

SIRTs

SIRT1: 120 μM; SIRT2: 100 μM; SIRT3: 50 μM; SIRT5: 150 μM; SIRT6: 184 μM

[183185]

3-Triazolylpyridine (3-TYP)

SIRT1; SIRT2; SIRT3

SIRT1: 0.088 μM; SIRT2: 0.092 μM; SIRT3: 0.016 μM

[186,187]

Sirtinol

SIRT1; SIRT2

SIRT1:131 μM; SIRT2: 38 μM

[188]

Salermide

SIRT1; SIRT2

SIRT1: 100 μM; SIRT2: 25 μM

[189]

Cambinol

SIRT1; SIRT2

SIRT1: 56 μM; SIRT2: 59 μM

[190]

Selisistat (EX 527)

SIRT1

38 nM

[191]

Inauhzin

SIRT1

0.72 μM

[192]

Thiomyristoyl

SIRT2

0.028 μM

[193]

Suramin

SIRT5

22 μM

[194]

Tenovin-1

SIRT1; SIRT2; SIRT3

SIRT1: 21 μM; SIRT2: 10 μM; SIRT3: 67 μM

[195]

Tenovin 6

SIRT1; SIRT2

SIRT1: 21 μM; SIRT2: 10 μM

[195]

AGK2

SIRT2

3.5 μM

[196]

SirReal2

SIRT2

0.14 μM

[197]

NAM treatment was reported to abolish Sir2p activities in yeast and could induce inhibition at a sufficiently high concentration, if it is assumed that it can be readily transported to cells [198]. NAM inhibits SIRT1 in chronic lymphocytic leukemia (CLL), leading to the blockade of CLL cells’ proliferation and induction of p53-mediated apoptosis [201]. NAM has also been reported to inhibit cell growth, proliferation, and promote apoptosis by targeting SIRT3 in OSCC cells [95], as well as targeting SIRT1 in prostate cancer cells [202]. A recent study conducted by Yousafzai and colleagues demonstrated that NAM potentiated the inhibition of cisplatin-induced viability and the activation of apoptosis in lung cancer cells [203]. NAM analogs, such as acridinedione derivatives (compound 4d) and 30 -phenethyloxy-2-anilino benzamide analogues (compound 33a and 33i), demonstrated anticancer effects by inhibiting SIRT1 and SIRT2 in breast and colon cancer cells, respectively [204,205]. 3-Triazolylpyridine (3-TYP) is another NAM analog which exhibits specific SIRT3 inhibitory activity, whilst also inhibiting both SIRT1 and SIRT2 protein activity. 3-TYP has exhibited a cytotoxic effect in the HeLa cervical cancer cell line [186,187]. 9.2.1.2 β-Naphthol-containing inhibitors β-Naphthol-containing inhibitors are a well-known category of SIRTi comprising the first generation of SIRTi. Some SIRTis such as Splitomicin and Sirtinol are commercial, while others like salermide, cambinol, and JGB1741 are still under research. Both Splitomicin and Sirtinol were identified through cell-based screens in Saccharomyces cerevisiae yeast by accessing Sir2p inhibition [206]. Splitomicin is a Sir2p inhibitor with a weak activity on human SIRTs. Splitomicin has a short half-life in vitro due to its labile δ-lactone toward aqueous hydrolysis in neutral conditions [207]. Splitomicin analogs, β-(4-methyl) phenyl-8-bromo-splitomicin and R-enantiomer of β-(4-methyl) phenyl-8-methyl-splitomicin, inhibit SIRT2 activity [208]. The Splitomicin analogs demonstrated an antiproliferative effect and induced α-tubulin hyperacetylation in breast cancer cells [208]. Another Splitomicin analogue, Benzodeazaoxaflavins, is a SIRT1/2 inhibitor that promotes apoptosis in leukemia cells and exhibits an antiproliferative effect in colon carcinoma and glioblastoma multiforme cancer stem cells [209]. Sirtinol 2-((2-Hydroxynaphthalen-1-yl methylene) amino)-N-(1-phenethyl) benzamide is a SIRT1 and SIRT2 inhibitor. Sirtinol is more potent against SIRT2 compared to SIRT1 [188]. Sirtinol inhibits cell proliferation, induces apoptosis and cell cycle arrest in breast, lung (NSCLC), adult T-cell leukemia-lymphoma (ATL), and colon cancer cells [210213]. Sirtinol has also been reported to sensitize prostate cancer and cervical cancer cells to cisplatin and camptothecin treatments [214,215]. Combination treatments of Sirtinol with sodium dichloroacetic acid (DCA) in NSCLC cells have been shown to synergistically induce G0/G1 phase arrest, enhance cancer cell death in vitro, and inhibit tumor growth in vivo [216].

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Salermide N-(3-[2-hydroxy-naphthalen-1-ylmethylene]-amino)-phenyl-2-phenyl-propionamide is a drug modified from Sirtinol which exhibits a greater inhibition of SIRT1 and SIRT2 compared to Sirtinol [189]. Salermide inhibits 80% of the enzymatic activity of SIRT1 and SIRT2 at a concentration of 100 and 25 μM, respectively [189]. Salermide treatment demonstrated a reduction of cell viability in a panel of cancer cells including leukemia, lymphoma, colon, and breast cancer cell lines. Salermide demonstrated a strong cytotoxic effect toward blood malignancy (MOLT4) cells but does not kill nontumorigenic cells (MRC5 cells). The main mechanism of Salermide is apoptosis induction via SIRT1 inhibition [189]. Cambinol inhibits SIRT1 and SIRT2 proteins whilst exhibiting a weak inhibitory activity against SIRT5 and no inhibition against SIRT3 [190]. Cambinol-mediated inhibition of SIRT1 sensitizes a NCI H460 lung cancer cell line to DNA-damaging agents (i.e., etoposide, paclitaxel) in a p53-independent manner by increasing the acetylation of p53, Ku70, and FOXO3a. Cambinol also induced apoptosis in Burkitt lymphoma cells and human HCC, as well as inhibiting tumor growth in tumor xenografts [190,217]. JGB1741, (4,5,6,7-tetrahydro-2-[(E)-[(2-hydroxy-1-naphthalenyl)methylene]amino]-N-(phenylmethyl)-benzo[b] thiophene-3-carboxamide) inhibits SIRT1 in K562, HepG2 and MDA-MB 231 cancer cell lines [218]. 9.2.1.3 Indole derivatives Indole is a heterocyclic bioactive moiety that is widely found in nature, amino acids (e.g., tryptophan), animal hormones (e.g., melatonin), and plant hormones (e.g., indol-3-ylacetic acid/auxin). The indole group consists of a number of SIRTis containing an indole moiety [219]. EX-527 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) was the first potent, selective, and cellpermeable SIRT1i, screened using a bacterial-expressed recombinant human SIRT1 [191,220]. EX-527 strongly inhibits SIRT1, but displays a weak potency against SIRT2 and SIRT3 [191]. Upon the release of nicotinamide from the SIRT1 enzyme postcatalysis, EX-527 prevents the release of both products, deacetylated peptide and O-acetyl-ADP-ribose, from the enzyme [9]. However, the use of EX-527 as a single agent with concentrations up to 100 μM did not increase the level of p53 upon SIRT1 inhibition [195]. By exposing the SIRT1 abundant, p53 wild-type human NSCLC cell lines to DNA-damage agents, the inhibition of SIRT1 by EX-527 conversely led to an increase in p53 acetylation. At the same time, no p53-mediated cell survival or cell proliferation was detected [221]. EX-527 exhibited a strong antiproliferative effect in pancreatic cancer cells [222,223]. EX-527 was reported to enhance the sensitivity of pancreatic cancer cells to gemcitabine treatment by inducing DNA damage with micronuclei formation and elevation of apoptotic cell death [223]. Zhang and coworkers also reported that EX-527 sensitizes pancreatic cancer cells to gemcitabine treatment by a significantly inducing G0/G1 cycle arrest, senescence, and apoptosis [222]. In addition, EX-527 also increased the chemosensitivity of drug-resistant lung cancer cells (H460-R) to cisplatin treatment [203], as well as induced G1 phase cell cycle arrest in cervical cancer cells [224,225]. EX-527 inhibited SIRT1 in H460-R cells leading to an increase of X-ray cross-complementing-1 (XRCC1) ubiquitination, which promotes chemoresistance in lung cancer [203]. Inauzhin, 10-[2-(5H-[1,2,4] triazino[5,6-b] indol-3-ylthio)butanoyl]-10H-phenothiazine inhibits SIRT1 and leads to p53 acetylation [192]. It was demonstrated that this results in a reduction in cell viability across a panel of cancer cell lines including human lung, ovarian, colon, osteosarcoma, glioma, and breast cancer. Inauzhin inhibits cell proliferation and induces senescence and apoptosis through a p53-dependent mechanism [192]. Inauzhin was also shown to suppress tumor growth in xenograft models derived from human lung cancer H460 and colon cancer HCT 116 cells. BZD9L1 is a benzimidazole derivative SIRTi that inhibits SIRT1 and is more potent against SIRT2 [226]. According to Yoon et al., inhibition of SIRT1 and SIRT2 resulted in hyperacetylation of α-tubulin with no obvious changes in p53. One unique feature of this SIRTi is its autofluorescent properties which can be used for pharmacokinetic studies. BZD9L1 exerts cytotoxic activity against colorectal, leukemia, and breast cancer cells. The mechanism of BZD9L1 in monitoring CRC cells growth has been thoroughly studied in vitro [148]. BZD9L1 inhibits cell proliferation and migration, and promotes apoptosis without inducing cell cycle arrest in CRC cell lines. Combination treatment of BZD9L1 with 5-FU synergistically reduced CRC cell viability and induced cell cycle arrest, senescence, micronucleation, and apoptosis in HCT 116 CRC cells [227]. Combination treatment of BZD9L1 and 5-FU was also demonstrated to inhibit tumor growth in a HCT 116 CRC tumor xenograft [227]. Other indole derivative of SIRTis include AC-93253 [228] and GW5074 [229,230]. AC-93253 is a highly potent SIRT2i which also possesses inhibitory activity against SIRT1 and SIRT3 [228]. AC-93253 exhibits potent cytotoxic effects towards prostate, lung, and pancreatic cancer cells in nanomolar concentration ranging from 10 to 100 nM. AC-93252 treatment leads to an upregulation of acetylated α-tubulin and hyperacetylation of p53 in NCI-H460 cells.

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9.2.1.4 Thioacyllysine-containing compounds Thioacyllysine-containing compounds inhibit SIRT activities by forming a covalent ADP-ribose-adduct (10 -S-alkylimidate intermediate) at the active site to block the SIRT-catalyzed deacetylation reaction [231]. BH-TM-4 is a thioacyllysine-containing SIRTi targeting SIRT13 and SIRT6 [193]. Among them, BHJH-TM4 is the potent cell-permeable SIRT6 inhibitor which also inhibits SIRT1, SIRT2, and SIRT3 [193]. Nε-thioacetyl-lysinecontaining tri-, tetra-, and pentapeptides are α-tubulin- and p53-based SIRTis with potent SIRT1 and SIRT2 inhibitory activities [232]. The most potent SIRT2i discovered by Kiviranta et al. is H-K-K(ε-thioAc)-L-A. A few potent SIRT1is have also been developed, exhibiting an equipotency to EX-527. The histone H3 lysine 9 (H3K9) thiosuccinyl peptide (H3K9TSu) inhibits SIRT5 with no inhibitory activities against SIRT13 [233]. Thiomyristoyl (TM) strongly inhibits SIRT2 but weakly inhibits SIRT1 and exhibits no activity against SIRT3 [84]. TM inhibition of SIRT2 leads to an increase of acetylated α-tubulin in breast cancer cells as well as downregulated c-MYC in various cancer cell lines. TM also inhibits tumor growth in vivo [84]. Compound 27 and 30 from Mellini and coworkers were SIRT is shown to be cell-permeable and nontoxic against SIRT13 [234]. Both compound 27 and 30 inhibit cell proliferation and induce cell cycle arrest at the G1 phase of breast cancer (MCF-7) and ARPE-19 cells [234]. Although thioacyllysine-containing compounds have effective inhibition properties, their poor selectivity, weak cell permeability, and instability have limited further development into potential drug candidates [235].

9.2.1.5 Tenovin Tenovin-1 and its water-soluble analog, Tenovin-6 are small molecules that activate p53 via inhibition of SIRT1 and SIRT2 [195]. Tenovin-1 increases p53 protein expression and the p53 downstream target p21CIP1/WAF1 protein through SIRT1 inhibition. Tenovin-1 is more cytotoxic against p53 wild-type cells including the BL2 Burkitt’s lymphoma cells, NTera2D cells, HCT 116 CRC cells, and ARN8 melanoma cells [195]. Compared to Tenovin-1, Tenovin-6 exhibits a greater inhibiting capacity against SIRT1 and SIRT2 [195]. Tenovin-6 has been demonstrated to be more cytotoxic against ARN8 melanoma cells than Tenovin-1, inhibiting the growth of ARN8-derived xenograft tumors [195] and neuroblastoma xenografts [236]. Many studies have also demonstrated Tenovin-6 to effectively induce apoptosis in various cancer cells such as colon cancer, uveal melanoma, B-cell lymphoma, acute lymphoblastic leukemia, and gastric cancer cells [237241]. Besides enhancing the apoptotic effect in cancer cells, Tenovin-6 has also been shown to suppress cancer cell proliferation, inhibit migration, and block autophagy in vitro [238,239,242]. Tenovin-6 is also an effective adjuvant in combination therapies. Synergistic anticancer effects have been observed in a HCT 116 tumor xenograft treated with Tenovin-6 and oxaliplatin or 5-FU combination treatment [237]. In addition, Tenovin-6 combined with metformin synergistically induced caspase-3dependent apoptosis in NSCLC cells [243]. Combined treatment of Tenovin-6 and BCR-ABL tyrosine kinase inhibitors (TKI), imatinib, significantly improved survival in mice xenografts and increased apoptosis in imatinib-resistant chronic myelogenous leukemia (CML) stem and progenitor cells in vivo [244]. The development of Tenovin-6 as single-agent treatment option is limited by its low specificity; however, Tenovin-6 is a good agent to be used in combination treatments [243,244]. Tenovin-D3 is an analog of Tenovin-6 [245]. Unlike Tenovin-6, which functions as a SIRT1i, Tenovin-D3 does not increase p53 levels or transcription factor activity but inhibits SIRT2 which contributes to the elevation of acetylated α-tubulin and p53-independent induction of p21CIP1/WAF1 (CDKN1A) [245].

9.2.1.6 Suramin Suramin (8,80 -[carbonylbis [imino-3,1-phenylenecarbonylimino (4-methyl-3,1-phenylene) carbonylimino]] bis-1,3,5-naphtalenetrisulfonic acid) is a symmetric polyanionic naphthylurea originally developed for trypanosomiasis and onchocerciasis treatments [221]. Suramin is a SIRT5i [194]. Suramin showed anticancer activities by inhibiting cell proliferation and inducing angiogenesis in adrenocortical cancer, human brain-metastatic melanoma, cervical, and ovarian cancer [246248]. However, Suramin is not a specific inhibitor targeting only SIRTs, but also targets other proteins such as the heparinase (HPA) enzyme [248] and cell surface receptors (e.g., EGFR and PDGFR) [249]. Suramin is currently under phase 1 clinical trial for bladder cancer, but not as a SIRTi [250,251]. Although Suramin analogs, such as aminoanthranilic acid derivative (NF675), exhibit preferential inhibitory activity against SIRT1 and SIRT2, suramin and its analogs have a highly polar sulfonic acid structure which causes cell impermeability and limits their use as a SIRTi [194]. In addition, Suramin induces serious systemic side effects including neurologic toxicity, which has restrained its clinical use [251].

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9.2.1.7 Other SIRTi 9.2.1.7.1 AGK2

AGK2 (2E)-2-cyano-3-[5-(2,5-dichlorophenyl)furan-2-yl]-N-(quinolin-5-yl)prop-2-enamide is a SIRT2i with reported slight inhibition of SIRT1 and SIRT3 [196]. AGK2 displayed anticancer activities in cervical cancer [224] and glioma cells [252]. AGK2 downregulates both SIRT1 and SIRT2 protein expression and triggers sub-G0 phase arrest, leading to an increase in cervical cancer cells death [224]. The AGK2 and DCA combination treatment has been demonstrated to synergistically inhibit 80%90% of NSCLC cancer cell survival by inhibiting SIRT2 [216]. 9.2.1.7.2 MHY2256

MHY2256 showed potent inhibition against SIRT1. MHY2256 decreased the viability of breast (MCF-7) and ovarian (SKOV-3) cells after a 48-h treatment period [253]. MHY2256 significantly induced cell cycle arrest in the G1 phase, leading to an effective increase in apoptotic cell death in MCF-7 and SKOV-3 cells. MHY2256 treatment also resulted in a significant increase in acetylated p53, upregulated LC3-II, and induced autophagic cell death in MCF7 tumor xenograft model. 9.2.1.7.3 SirReal2

Sirtuin-rearranging ligands 2 (SirReal2) is a family of aminothiazoles that selectively inhibits SIRT2 [197]. Binding of SirReal2 to the SIRT2 protein leads to the rearrangement of its active site and locking it in an open conformation. Incubation of HeLa cells with SirReal2 showed an increase expression of acetylated α-tubulin and a downregulation of BubR1. 9.2.1.7.4 MC2494

MC2494, 3-(4-(2-chlorobenzoyl)-1H-pyrrol-2-yl)-2-cyano-N-(quinolin-5-yl) acrylamide, inhibits both SIRT1 and SIRT2. MC2494 was recently found to be a pan-SIRT1 inhibitor which displays promising anticancer activity in vitro, in vivo (xenograft and allograft cancer models), and in leukemic blasts ex vivo [254]. MC2494 inhibits cancer cell proliferation and migration, induces apoptosis, and suppresses tumor growth [254,255]. 9.2.1.7.5 Toxoflavin

Toxoflavin, also known as xanthothricin, is a SIRT1/2 inhibitor with higher inhibition against SIRT1 than SIRT2. Toxoflavin was originally identified as a toxin produced by bacteria with antibiotic function. Toxoflavin has been demonstrated to exhibit cytotoxic effects in various cancer cells including NSCLC, breast, prostate, ovarian, gastric, central nervous system, leukemia, and pancreatic cancer cells [256]. Toxoflavin is an electron-carrier which facilitates H2O2 production during glycolysis and the citric acid cycle [257]. The H2O2 produced accounts for its poison and nonspecific toxicity effects, limiting its clinical development.

9.2.2 Sirtuin activators The mechanism by which STACs activate SIRTs remains controversial. Two opposing models have been proposed to account for STAC activity: (1) direct allosteric activation of SIRTs through the lowering of peptide substrate Km, and/or (2) indirect activation resulting from off-target effects [258261]. There are two different types of STACs: natural and synthetic. Chalcones, flavones, and stilbenes are plant polyphenols which were the first natural SIRT1 STACs discovered in 2003 [262266]. As research on SIRTs progressed over the years, synthetic STACs were also developed. The different classes of synthetic STACs consist of imidazothiazoles, oxazolopyridine, thiazolopyridines, benzimidazoles, and bridged ureas [235,263]. These STACs activate SIRTs allosterically [235]. The more commonly known synthetic STACs which are commercially available and reported to target cancer include SRT1720, SRT3025, SRT1460, SRT2183, and UBCS039 [235,267270]. The drugs which have been developed to target and activate SIRTs are mainly focused on antiaging, antiinflammatory, antidiabetic, and antiobesity activity. Resveratrol (RSV) is a natural polyphenol compound containing two phenyl rings separated by a methylene bridge. RSV has been found in many plants, such as cranberries, grapes, peanuts, and Japanese giant knotweed [271]. The anticancer roles of RSV have been widely studied and indicate that RSV can inhibit tumorigenesis by inducing S-phase cell cycle arrest and apoptosis, as well as inhibiting metastasis, aromatase, and angiogenesis in liver, breast, prostate, leukemia, skin, and myeloma cancer cells [271,272].

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Despite SIRT1 being the most studied SIRT and possessing a wide range of activators and inhibitors, SIRT1 still yields controversial results regarding whether or not its activation or inhibition can produce an anticancer effect [273275]. SIRT1 deficiency induced an abnormal accumulation of cells in the early phases of mitosis-impaired DNA damage repair, and chromosome instability which could subsequently cause cancer [60]. RSV is a potent SIRT1 agonist with implicated antitumor capability. RSV regulates SIRT1 through the AMP-dependent kinase (AMPK) pathway which activates SIRT1 by increasing the intracellular concentration of NAD1 [273,276]. Wang and colleagues have previously shown that in vivo SIRT11/2; p531/2 mice xenograft models with different malignancy types (i.e. sarcomas, lymphomas, teratomas, and carcinomas) exhibited SIRT1 activation after treatment with RSV, which in turns effectively inhibited the tumorigenesis of SIRT11/2; p531/2 mice [60]. RSV treatment in highproliferative SIRT1 knockdown prostate cancer cells have a reverse effect by inhibiting cancer cells’ growth and proliferation [277]. This study also reported that RSV treatment induces autophagy through SIRT1/S6K pathways and inhibits the incidence of precursor lesions of prostate cancer through the Akt/mTOR signaling pathway [277]. RSV was also reported to reduce cell viability and induce apoptosis in siRNA-SIRT1 transfected human chondrosarcoma (a malignant primary bone tumor) cells, via activation of caspase-3 and inhibition of NF-kB pathways [278]. Besides, RSV has been shown to alleviate EMT processes in lung and ovarian cancer in vitro and in vivo [279,280]. Expression of SIRT1 was suppressed in these two cancer cell lines due to hypoxic stress, thus promoting EMT. RSV activates SIRT1 expression which consequently overcomes the SUMOylation-mediated EMT process [279,280]. Although increased evidence indicates RSV to be an effective SIRT1 activator with anticancer properties, its poor solubility, low bioavailability, rapid elimination, and unwanted toxicity effects are the major factors that limit its development as a cancer drug candidate [281]. Alternatively, synthetic STACs such as SRT2170 and SIRT1460 have been synthesized to overcome the RSV limitation. These synthetic STACs are potent SIRT1 activators with 800- to 1000-fold efficacy compared to RSV [259,267]. SRT1720 has been shown to reduce cancer cell viability and sensitize cancer cells to chemotherapy drugs. A study conducted by Sonnemann and coworkers demonstrated that combination treatments of SRT1720 with chemotherapy drugs largely enhanced etoposide- and vincristine-induced cell death, whereas RSV inhibited cell death in Ewing’s sarcoma cells [282]. Furthermore, another study also reported an enhanced effect when SRT1720 was used in combination with dexamethasone or bortezomib [269,283]. SRT1720 induced apoptosis in multiple cancer cells including breast and myeloma [283,284] through the increase in SIRT1 deacetylase activity. SRT1720 induced apoptosis through caspase 8/9/3 activation and ATM-CHK2 signaling pathways which will subsequently inhibit the NF-κB signaling pathway, which otherwise maintains cell growth and survival [283]. Similarly, SRT1720 was shown to inhibit the growth of pancreatic cancer in vitro and in vivo through a SIRT1lysosomal-dependent apoptotic pathway in another study [285]. This study also reported that SRT1460 and SRT3025 were effective in inhibiting the growth and survival of pancreatic cancer. SRT1720 and SRT3025 were shown to potently hinder cell survival when used in adjunction with paclitaxel and gemcitabine, whereas SRT1460 only showed equal potency when used alone [285]. However, SRT1720 has also been reported to promote breast cancer metastasis [274], suggesting that the effects of STACs may function in the opposite manner. Thus further evaluation of STACs activity in a cancer-specific manner is required. SIRT1 STACs, SRT2183, and SRT501 have demonstrated significant inhibition of growth and induction of apoptosis in malignant lymphoid cell lines. Furthermore, a significant inhibition of growth and induction of apoptosis were demonstrated in malignant lymphoid cell lines when these compounds were used in adjunct with panobinostat [275]. It is noteworthy that SRT501 is an improved formulation of RSV possessing improved bioavailability [270,273]. UBCS039 is a newly synthesized pyrrolo[1,2-a]quinoxaline derivative, the first synthetic SIRT6 activator [286]. UBCS039 was reported to activate SIRT6 activities without affecting its expression level regardless of cancer histotype [287]. UBCS039 induced a time-dependent activation of autophagy in various cancer cells, such as human NSCLC, fibrosarcoma, colon, HeLa, and epithelial cervix carcinoma [287]. Iachettini and colleagues reported that UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity. In this study, antioxidants such as NAC or Trolox were reported to completely counteract UBCS039-induced autophagy, indicating that increased ROS had a key role in upstream events that commit the cells to autophagy. A sustained activation of SIRT6 as a result of UBCS039 treatment also resulted in autophagy-related cell death [287]. Another recent SIRT6 activator that has been discovered is MDL-800 [288]. Huang et al. reported that MDL-800 increases the deacetylase activity of SIRT6 by up to 22-fold via binding to an allosteric site. The activation of SIRT6 by MDL-800 inhibits cell proliferation and induces cell cycle arrest in HCC. The in vivo study of MDL-800 in a HCC tumor xenograft model and in SIRT6 KO mice also demonstrated a significant impediment of tumor growth by activating the deacetylase activity of SIRT6 [288].

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9.3 Conclusion and future perspectives SIRTs are important biological regulators that are implicated in many cellular processes. Their physiological functions and critical roles in maintaining genome stability and stress responses are fundamental in the onset of most cancers. SIRTs are also the command centre regulating the signaling pathways which are highly associated with tumor development. The molecular mechanisms of SIRTs are yet to be fully elucidated. For instance, some SIRTs share common targets and regulate the same cellular process in either the same or different contexts, suggesting that they could demonstrate synergistic or antagonistic effects among each other when responding to stress. SIRTs also have a dual role in regulating tumor initiation and progression. These sometimes-contradictory roles of SIRTs in cancer are highly dependent on the tumor type and tumor microenvironment. However, knowledge of what specific factors in the cancer type and stroma that underpin the oncogenic or suppressor roles of SIRTs is still far from complete. Over the last decade, the dual roles of SIRT1 have been extensively studied in many cancers, which in turn has provided us with some ideas on the mechanisms of SIRTs in cancer modulation. However, the dual roles of other SIRTs in cancer are not well established and remain largely unresolved. Efforts to identify the unique functionality of each SIRT in the bid to unravel how different SIRTs regulate the cancer biological processes and signaling pathways are critical steps toward the development of effective SIRT-targeting cancer therapies. Depending on their specific roles as oncogenics or tumor suppressors, targeting SIRTs is a potential therapeutic option in sensitizing tumor cells to anticancer treatments. The discovery and development of novel and highly specific SIRT modulators will facilitate the development of an effective cancer therapy. The commercially available SIRTi are well-known for their inhibitory activities against SIRT1/2, which affect the acetylation of p53 and α-tubulin, to produce anticancer effects. These SIRTi inhibitors target the NAD1 binding site in the active site of SIRT protein. Nevertheless, most of the SIRT modulators have not been tested against other SIRT family members. These SIRT inhibitors may lack selectivity, the requisite pharmacological properties, or fail to display a significant potency with high micromolar IC50, ultimately limiting their potential for the development as treatment modalities. Growing evidence has indicated that the anticancer effects of available SIRTis are most likely be attributed to the nonspecific targeting of multiple SIRTs at once. This action may improve treatment outcomes but may also induce antagonist effects and unwanted toxicity consequences. The other aspect that deserves consideration includes its effects against the other NAD1-consuming proteins, such as poly(ADP-ribosyl) polymerases (PARPs) and cyclic ADP-ribose synthases (CD38 and CD157). In addition, little is known about how these commercially-available SIRTis affect the NAD1-consuming proteins. Thus the polypharmacology properties of SIRTi are an important factor to understand in order to establish the feasible use of SIRTi in anticancer therapies. Moreover, only tenovin, cambinol, and inauhzin have demonstrated an anticancer effect in in vivo models. At the same time, none of these SIRTis has entered clinical trials as possible anticancer agents. Therefore, research emphasised on developing a highly potent, specific, and low-toxic SIRTi is crucial. SIRTs are highly dependent on NAD1 for their activities, therefore the activation of SIRTs could lead to an overconsumption or overproduction of NAD1, resulting in many downstream effects, given that SIRTs are implicated in several pathways. Furthermore, SIRT activation is not necessarily therapeutic in all types of cancer as it has shown contrasting reports in different cancer types, though there is still plenty of work to be done to fully understand the nature of SIRTs activation. The potential for SIRT activation as a possible anticancer treatment is a huge therapeutic step in cancer therapy. Many studies have also emphasised on SIRT inhibition as an anticancer therapy, underscoring the need for research on SIRT activation as a potential therapeutic strategy. All together, these warrant further investigations to elucidate the mechanisms of SIRT activity in diverse cancer types and in cancers harbouring different mutations before directing attention towards the development of an activator or inhibitor. The lack of efficient enzymatic activity assays has also limited the development of SIRT modulators, especially for SIRT47 family members. Structural proteomics is one of the important aspects that can be employed to address the unresolved issues of SIRT members. In silico studies involving the use of bioinformatics tools, docking, and molecular modeling can enhance the understanding on the intricate relationships among the SIRT family members. The information derived from analyses of the SIRT/effector complexes is also essential to uncover the mechanism underlying SIRT inhibition and/or activation, which in turn facilitates the structure-based design of specific SIRT modulators with therapeutic potential. In vitro and in vivo studies involving the overexpression, knockdown, or knockout of SIRTs may also provide a deeper insight into the molecular functions of this protein family. Collectively, better characterization and understanding of each SIRT family member is crucial to fill the knowledge gaps between SIRTs and malignancy.

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Acknowledgment The authors would like to acknowledge Chris Malajczuk from the Biomolecular Modeling Group in the School of Pharmacy and Biomedical Sciences at Curtin University for proofreading the manuscript.

References [1] Alhazzazi T, Kamarajan P, Verdin E, Kapila Y. SIRT3 and cancer: tumor promoter or suppressor? Biochim Biophys Acta 2011;1816:808. [2] Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403(6771):795800. [3] Saunders LR, Verdin E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 2007;26(37):5489504. [4] Martı´nez-Redondo P, Vaquero A. The diversity of histone versus nonhistone sirtuin substrates. Genes Cancer 2013;4(34):14863. [5] Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J 2007;404(1):113. [6] Bosch-Presegue´ L, Vaquero A. The dual role of sirtuins in cancer. Genes Cancer 2011;2(6):64862. [7] Nakagawa T, Guarente L. Sirtuins at a glance. J Cell Sci 2011;124(6):833. [8] Choi J-E, Mostoslavsky R. Sirtuins, metabolism, and DNA repair. Curr Opin Genet Dev 2014;26:2432. [9] Carafa V, Altucci L, Nebbioso A. Dual tumor suppressor and tumor promoter action of sirtuins in determining malignant phenotype. Front Pharmacol 2019;10(38):114. [10] Bosch-Presegue L, Vaquero A. Sirtuins in stress response: guardians of the genome. Oncogene 2014;33(29):376475. [11] Carafa V, Nebbioso A, Altucci L. Sirtuins and disease: the road ahead. Front Pharmacol 2012;3:4. [12] Yuan H, Su L, Chen WY. The emerging and diverse roles of sirtuins in cancer: a clinical perspective. OncoTargets Ther 2013;6:1399416. [13] Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 2008;135(5):90718. [14] Ming M, Shea CR, Guo X, Li X, Soltani K, Han W, et al. Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. Proc Natl Acad Sci U S A 2010;107(52):226238. [15] Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature 2001;411(6835):36674. [16] Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2006;124(2):31529. [17] Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 2010;1:3. [18] Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell 2008;32(1):1120. [19] Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxiainducible factor 1alpha. Mol Cell 2010;38(6):86478. [20] Srisuttee R, Koh SS, Kim SJ, Malilas W, Boonying W, Cho IR, et al. Hepatitis B virus X (HBX) protein upregulates beta-catenin in a human hepatic cell line by sequestering SIRT1 deacetylase. Oncol Rep 2012;28(1):27682. [21] Yuan J, Minter-Dykhouse K, Lou Z. A c-Myc-SIRT1 feedback loop regulates cell growth and transformation. J Cell Biol 2009; 185(2):20311. [22] Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One 2008;3(4):e2020. [23] Mao B, Zhao G, Lv X, Chen HZ, Xue Z, Yang B, et al. Sirt1 deacetylates c-Myc and promotes c-Myc/Max association. Int J Biochem Cell Biol 2011;43(11):157381. [24] Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 2004;116(4):55163. [25] van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem 2004;279(28):288739. [26] Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1 {alpha}. J Biol Chem 2005;280(16):1645660. [27] Yang Y, Hou H, Haller EM, Nicosia SV, Bai W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J 2005;24(5):102132. [28] Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;303(5666):201115. [29] Salminen A, Kaarniranta K. SIRT1: regulation of longevity via autophagy. Cell Signal 2009;21(9):135660. [30] Powell MJ, Casimiro MC, Cordon-Cardo C, He X, Yeow WS, Wang C, et al. Disruption of a Sirt1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation. Cancer Res 2011;71(3):96475. [31] Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004;303(5663):14837. [32] Lin Z, Gao C, Ning Y, He X, Wu W, Chen YG. The pseudoreceptor BMP and activin membrane-bound inhibitor positively modulates Wnt/beta-catenin signaling. J Biol Chem 2008;283(48):330538. [33] Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997;275(5307):178790. [34] Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, et al. Constitutive transcriptional activation by a beta-cateninTcf complex in APC2/2 colon carcinoma. Science 1997;275(5307):17847. [35] Cho IR, Koh SS, Malilas W, Srisuttee R, Moon J, Choi YW, et al. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of beta-catenin. Biochem Biophys Res Commun 2012;423(2):2705.

II. Sirtuins and cancer

170

9. The bifunctional roles of sirtuins and their therapeutic potential in cancer

[36] Salaroli R, Di Tomaso T, Ronchi A, Ceccarelli C, Cammelli S, Cappellini A, et al. Radiobiologic response of medulloblastoma cell lines: involvement of beta-catenin? J Neurooncol 2008;90(3):24351. [37] Chen LF, Mu Y, Greene WC. Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. EMBO J 2002; 21(23):653948. [38] Kiernan R, Bres V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, et al. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J Biol Chem 2003;278(4):275866. [39] Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 2004;23(12):236980. [40] Yang L, Zhang J, Yan C, Zhou J, Lin R, Lin Q, et al. SIRT1 regulates CD40 expression induced by TNF-alpha via NF-kB pathway in endothelial cells. Cell Physiol Biochem 2012;30(5):128798. [41] An Y, Kiang A, Lopez JP, Kuo SZ, Yu MA, Abhold EL, et al. Cigarette smoke promotes drug resistance and expansion of cancer stem cell-like side population. PLoS One 2012;7(11):e47919. [42] Yang SR, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I. Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am J Physiol Lung Cell Mol Physiol 2007;292(2):L56776. [43] Di Sante G, Pestell TG, Casimiro MC, Bisetto S, Powell MJ, Lisanti MP, et al. Loss of Sirt1 promotes prostatic intraepithelial neoplasia, reduces mitophagy, and delays PARK2 translocation to mitochondria. Am J Pathol 2015;185(1):26679. [44] Leko V, Park GJ, Lao U, Simon JA, Bedalov A. Enterocyte-specific inactivation of SIRT1 reduces tumor load in the APC(1/min) mouse model. PLoS One 2013;8(6):e66283. [45] Laemmle A, Lechleiter A, Roh V, Schwarz C, Portmann S, Furer C, et al. Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1alpha protein under hypoxic conditions. PLoS One 2012;7(3):e33433. [46] Menssen A, Hydbring P, Kapelle K, Vervoorts J, Diebold J, Luscher B, et al. The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. Proc Natl Acad Sci U S A 2012;109(4):E18796. [47] Long Q, Xu J, Osunkoya AO, Sannigrahi S, Johnson BA, Zhou W, et al. Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence. Cancer Res 2014;74(12):322837. [48] Deng CX. SIRT1, is it a tumor promoter or tumor suppressor? Int J Biol Sci 2009;5(2):14752. [49] Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001;107(2):14959. [50] Bouras T, Fu M, Sauve AA, Wang F, Quong AA, Perkins ND, et al. SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem 2005;280(11):1026476. [51] Lin Z, Yang H, Kong Q, Li J, Lee SM, Gao B, et al. USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Mol Cell 2012;46(4):48494. [52] Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, et al. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 2002;21(10):238396. [53] Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998;67:75391. [54] Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000;103(2):295309. [55] Kume S, Haneda M, Kanasaki K, Sugimoto T, Araki S, Isshiki K, et al. SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation. J Biol Chem 2007;282(1):1518. [56] O’Brate A, Giannakakou P. The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist Updat 2003;6(6):31322. [57] Tanno M, Sakamoto J, Miura T, Shimamoto K, Horio Y. Nucleocytoplasmic shuttling of the NAD 1 -dependent histone deacetylase SIRT1. J Biol Chem 2007;282(9):682332. [58] Byles V, Chmilewski LK, Wang J, Zhu L, Forman LW, Faller DV, et al. Aberrant cytoplasm localization and protein stability of SIRT1 is regulated by PI3K/IGF-1R signaling in human cancer cells. Int J Biol Sci 2010;6(6):599612. [59] Wilking MJ, Singh C, Nihal M, Zhong W, Ahmad N. SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation. Arch Biochem Biophys 2014;563:94100. [60] Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 2008;14(4):31223. [61] Herranz D, Maraver A, Canamero M, Gomez-Lopez G, Inglada-Perez L, Robledo M, et al. SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency. Oncogene 2013;32(34):40526. [62] Wilking MJ, Ahmad N. The role of SIRT1 in cancer: the saga continues. Am J Pathol 2015;185(1):268. [63] Inoue T, Hiratsuka M, Osaki M, Yamada H, Kishimoto I, Yamaguchi S, et al. SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. Oncogene 2007;26(7):94557. [64] Inoue T, Nakayama Y, Yamada H, Li YC, Yamaguchi S, Osaki M, et al. SIRT2 downregulation confers resistance to microtubule inhibitors by prolonging chronic mitotic arrest. Cell Cycle 2009;8(8):127991. [65] Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, et al. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev 2006;20(10):125661. [66] Serrano L, Martinez-Redondo P, Marazuela-Duque A, Vazquez BN, Dooley SJ, Voigt P, et al. The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes Dev 2013; 27(6):63953. [67] Zhao E, Hou J, Ke X, Abbas MN, Kausar S, Zhang L, et al. The roles of sirtuin family proteins in cancer progression. Cancers (Basel) 2019;11(12):1949. [68] Nguyen P, Lee S, Lorang-Leins D, Trepel J, Smart DK. SIRT2 interacts with β-catenin to inhibit Wnt signaling output in response to radiation-induced stress. Mol Cancer Res 2014;12(9):124453. [69] Cui Y, Qin L, Wu J, Qu X, Hou C, Sun W, et al. SIRT3 enhances glycolysis and proliferation in SIRT3-expressing gastric cancer cells. PLoS One 2015;10:e0129834.

II. Sirtuins and cancer

References

171

[70] Xie HJ, Jung KH, Nam SW. Overexpression of SIRT2 contributes tumor cell growth in hepatocellular carcinomas. Mol Cell Toxicol 2011; 7(4):36774. [71] Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT, Zhang XD, et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ 2013;20(3):50314. [72] Huang S, Zhao Z, Tang D, Zhou Q, Li Y, Zhou L, et al. Downregulation of SIRT2 inhibits invasion of hepatocellular carcinoma by inhibiting energy metabolism. Transl Oncol 2017;10(6):91727. [73] McGlynn LM, Zino S, MacDonald AI, Curle J, Reilly JE, Mohammed ZM, et al. SIRT2: tumor suppressor or tumor promoter in operable breast cancer? Eur J Cancer 2014;50(2):290301. [74] Lai CC, Lin PM, Lin SF, Hsu CH, Lin HC, Hu ML, et al. Altered expression of SIRT gene family in head and neck squamous cell carcinoma. Tumor Biol 2013;34(3):184754. [75] Grbesa I, Pajares MJ, Martinez-Terroba E, Agorreta J, Mikecin AM, Larrayoz M, et al. Expression of sirtuin 1 and 2 is associated with poor prognosis in non-small cell lung cancer patients. PLoS One 2015;10(4):e0124670. [76] Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 2011;20(4):48799. [77] Chen J, Chan AW, To KF, Chen W, Zhang Z, Ren J, et al. SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3beta/beta-catenin signaling. Hepatology 2013;57(6):228798. [78] Du Y, Wu J, Zhang H, Li S, Sun H. Reduced expression of SIRT2 in serous ovarian carcinoma promotes cell proliferation through disinhibition of CDK4 expression. Mol Med Rep 2017;15(4):163846. [79] Ming M, Qiang L, Zhao B, He YY. Mammalian SIRT2 inhibits keratin 19 expression and is a tumor suppressor in skin. Exp Dermatol 2014;23(3):2079. [80] Peck B, Chen CY, Ho KK, Di Fruscia P, Myatt SS, Coombes RC, et al. SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther 2010;9(4):84455. [81] Wang Y, Mu Y, Zhou X, Ji H, Gao X, Cai WW, et al. SIRT2-mediated FOXO3a deacetylation drives its nuclear translocation triggering FasL-induced cell apoptosis during renal ischemia reperfusion. Apoptosis 2017;22(4):51930. [82] Xu L, Wang L, Zhou L, Dorfman RG, Pan Y, Tang D, et al. The SIRT2/cMYC pathway inhibits peroxidation-related apoptosis in cholangiocarcinoma through metabolic reprogramming. Neoplasia 2019;21(5):42941. [83] Li Y, Zhang M, Dorfman RG, Pan Y, Tang D, Xu L, et al. SIRT2 promotes the migration and invasion of gastric cancer through RAS/ ERK/JNK/MMP-9 pathway by increasing PEPCK1-related metabolism. Neoplasia 2018;20(7):74556. [84] Jing H, Hu J, He B, Negron Abril YL, Stupinski J, Weiser K, et al. A SIRT2-selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anticancer activity. Cancer Cell 2016;29(3):297310. [85] Yang MH, Laurent G, Bause AS, Spang R, German N, Haigis MC, et al. HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS. Mol Cancer Res 2013;11(9):10727. [86] Lombard DB, Alt FW, Cheng H-L, Bunkenborg J, Streeper RS, Mostoslavsky R, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 2007;27(24):880714. [87] Iwahara T, Bonasio R, Narendra V, Reinberg D. SIRT3 functions in the nucleus in the control of stress-related gene expression. Mol Cell Biol 2012;32(24):502234. [88] Chen Y, Fu LL, Wen X, Wang XY, Liu J, Cheng Y, et al. Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis 2014;5(2):e1047. [89] Xiong Y, Wang M, Zhao J, Wang L, Li X, Zhang Z, et al. SIRT3 is correlated with the malignancy of non-small cell lung cancer. Int J Oncol 2017;50(3):90310. [90] Torrens-Mas M, Pons DG, Sastre-Serra J, Oliver J, Roca P. SIRT3 silencing sensitizes breast cancer cells to cytotoxic treatments through an increment in ROS production. J Cell Biochem 2017;118(2):397406. [91] Choi J, Koh E, Lee YS, Lee HW, Kang HG, Yoon YE, et al. Mitochondrial Sirt3 supports cell proliferation by regulating glutaminedependent oxidation in renal cell carcinoma. Biochem Biophys Res Commun 2016;474(3):54753. [92] Liu C, Huang Z, Jiang H, Shi F. The sirtuin 3 expression profile is associated with pathological and clinical outcomes in colon cancer patients. BioMed Res Int 2014;2014:871263. [93] George J, Nihal M, Singh CK, Zhong W, Liu X, Ahmad N. Pro-proliferative function of mitochondrial sirtuin deacetylase SIRT3 in human melanoma. J Invest Dermatol 2016;136(4):80918. [94] Zhao Y, Yang H, Wang X, Zhang R, Wang C, Guo Z. Sirtuin-3 (SIRT3) expression is associated with overall survival in esophageal cancer. Ann Diagn Pathol 2013;17(6):4835. [95] Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D’Silva NJ, et al. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer 2011;117(8):16708. [96] Xiong Y, Wang M, Zhao J, Han Y, Jia L. Sirtuin 3: a Janus face in cancer. Int J Oncol 2016;49(6):222735. [97] Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 2011;19(3):41628. [98] Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010;17(1):4152. [99] Schumacker PT. SIRT3 controls cancer metabolic reprogramming by regulating ROS and HIF. Cancer Cell 2011;19(3):299300. [100] Desouki MM, Doubinskaia I, Gius D, Abdulkadir SA. Decreased mitochondrial SIRT3 expression is a potential molecular biomarker associated with poor outcome in breast cancer. Hum Pathol 2014;45(5):10717. [101] Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res 2010;44(5):47996. [102] Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010;12(6):6627. [103] Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010;143(5):80212.

II. Sirtuins and cancer

172

9. The bifunctional roles of sirtuins and their therapeutic potential in cancer

[104] Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 2010;40(6):893904. [105] Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014;53(4):53448. [106] Jing E, O’Neill BT, Rardin MJ, Kleinridders A, Ilkeyeva OR, Ussar S, et al. Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes 2013;62(10):340417. [107] Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G, et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 2013;498(7452):10912. [108] Kumari S, Badana AK, Malla R. Reactive oxygen species: a key constituent in cancer survival. Biomark Insights 2018;13 1177271918755391. [109] Torrens-Mas M, Oliver J, Roca P, Sastre-Serra J. SIRT3: oncogene and tumor suppressor in cancer. Cancers 2017;9(7):90. [110] Ozden O, Park SH, Kim HS, Jiang H, Coleman MC, Spitz DR, et al. Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. Aging (Albany NY) 2011;3(2):1027. [111] Zou X, Santa-Maria CA, O’Brien J, Gius D, Zhu Y. Manganese superoxide dismutase acetylation and dysregulation, due to loss of SIRT3 activity, promote a luminal B-like breast carcinogenic-permissive phenotype. Antioxid Redox Signal 2016;25(6):32636. [112] Grossi V, Fasano C, Celestini V, Lepore Signorile M, Sanese P, Simone C. Chasing the FOXO3: insights into its new mitochondrial lair in colorectal cancer landscape. Cancers 2019;11(3):414. [113] Allison SJ, Milner J. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle 2007;6(21):266977. [114] Song CL, Tang H, Ran LK, Ko BC, Zhang ZZ, Chen X, et al. Sirtuin 3 inhibits hepatocellular carcinoma growth through the glycogen synthase kinase-3beta/BCL2-associated X protein-dependent apoptotic pathway. Oncogene 2016;35(5):63141. [115] Tao NN, Zhou HZ, Tang H, Cai XF, Zhang WL, Ren JH, et al. Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway. Oncotarget 2016;7(31):5011730. [116] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):64674. [117] Li S, Banck M, Mujtaba S, Zhou MM, Sugrue MM, Walsh MJ. p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS One 2010;5(5):e10486. [118] Ashraf N, Zino S, Macintyre A, Kingsmore D, Payne AP, George WD, et al. Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer 2006;95(8):105661. [119] Cheng Y, Ren X, Gowda AS, Shan Y, Zhang L, Yuan YS, et al. Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress. Cell Death Dis 2013;4(7):e731. [120] Mahlknecht U, Voelter-Mahlknecht S. Fluorescence in situ hybridization and chromosomal organization of the sirtuin 4 gene (Sirt4) in the mouse. Biochem Biophys Res Commun 2009;382(4):68590. [121] Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells. Cell 2006;126(5):94154. [122] Anderson KA, Huynh FK, Fisher-Wellman K, Stuart JD, Peterson BS, Douros JD, et al. SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab 2017;25(4):83855 e15. [123] Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 2013;50(5):68698. [124] Mathias RA, Greco TM, Oberstein A, Budayeva HG, Chakrabarti R, Rowland EA, et al. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 2014;159(7):161525. [125] Miyo M, Yamamoto H, Konno M, Colvin H, Nishida N, Koseki J, et al. Tumor-suppressive function of SIRT4 in human colorectal cancer. Br J Cancer 2015;113(3):4929. [126] Hu Y, Lin J, Lin Y, Chen X, Zhu G, Huang G. Overexpression of SIRT4 inhibits the proliferation of gastric cancer cells through cell cycle arrest. Oncol Lett 2019;17(2):21716. [127] Blaveri E, Simko JP, Korkola JE, Brewer JL, Baehner F, Mehta K, et al. Bladder cancer outcome and subtype classification by gene expression. Clinical Cancer Res: Off J Am Assoc Cancer Res 2005;11(11):404455. [128] Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, et al. Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A 2001;98(24):137849. [129] Nakahara Y, Yamasaki M, Sawada G, Miyazaki Y, Makino T, Takahashi T, et al. Downregulation of SIRT4 expression is associated with poor prognosis in esophageal squamous cell carcinoma. Oncology 2016;90(6):34755. [130] Daye D, Wellen KE. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol 2012;23 (4):3629. [131] Zaganjor E, Vyas S, Haigis MC. SIRT4 is a regulator of insulin secretion. Cell Chem Biol 2017;24(6):6568. [132] Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013;23(4):45063. [133] Jeong SM, Lee A, Lee J, Haigis MC. SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. The J Biol Chem 2014;289(7):413544. [134] Fu L, Dong Q, He J, Wang X, Xing J, Wang E, et al. SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway. Oncogene 2017;36(19):272436. [135] Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 2010;11(12):87284. [136] Huang G, Lin Y, Zhu G. SIRT4 is upregulated in breast cancer and promotes the proliferation, migration and invasion of breast cancer cells. Int J Clin Exp Pathol 2017;10(12):1184956. [137] Jeong SM, Hwang S, Seong RH. SIRT4 regulates cancer cell survival and growth after stress. Biochem Biophys Res Commun 2016; 470(2):2516. [138] Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 2009;137(3):56070.

II. Sirtuins and cancer

References

173

[139] Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 2014;19(4):60517. [140] Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 2011;334(6057):8069. [141] Nishida Y, Rardin MJ, Carrico C, He W, Sahu AK, Gut P, et al. SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol Cell 2015;59(2):32132. [142] Lin ZF, Xu HB, Wang JY, Lin Q, Ruan Z, Liu FB, et al. SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochem Biophys Res Commun 2013;441(1):1915. [143] Chen XF, Tian MX, Sun RQ, Zhang ML, Zhou LS, Jin L, et al. SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer. EMBO Rep 2018;19(5):e45124. [144] Guo D, Song X, Guo T, Gu S, Chang X, Su T, et al. Vimentin acetylation is involved in SIRT5-mediated hepatocellular carcinoma migration. Am J Cancer Res 2018;8(12):2453. [145] Wang Y, Shi J, Chai K, Ying X, Zhou BP. The role of snail in EMT and tumorigenesis. Curr Cancer Drug Targets 2013;13(9):96372. [146] Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell 2014;14(3):27591. [147] Bringman-Rodenbarger LR, Guo AH, Lyssiotis CA, Lombard DB. Emerging roles for SIRT5 in metabolism and cancer. Antioxid Redox Signal 2018;28(8):67790. [148] Wang Y-Q, Wang H-L, Xu J, Tan J, Fu L-N, Wang J-L, et al. Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner. Nat Commun 2018;9(1):115. [149] Lu W, Zuo Y, Feng Y, Zhang M. SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer. Tumor Biol 2014;35(11):10699705. [150] Sun X, Wang S, Gai J, Guan J, Li J, Li Y, et al. SIRT5 promotes cisplatin resistance in ovarian cancer by suppressing DNA damage in a ROS-dependent manner via regulation of the Nrf2/HO-1 pathway. Front Oncol 2019;9:754. [151] Zhang R, Wang C, Tian Y, Yao Y, Mao J, Wang H, et al. SIRT5 promotes hepatocellular carcinoma progression by regulating mitochondrial apoptosis. J Cancer 2019;10(16):387182. [152] Lerrer B, Gertler AA, Cohen HY. The complex role of SIRT6 in carcinogenesis. Carcinogenesis 2016;37(2):10818. [153] Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 2005;280 (22):2131320. [154] Van Meter M, Mao Z, Gorbunova V, Seluanov A. Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair. Aging 2011; 3(9):82935. [155] Bu¨tepage M, Eckei L, Verheugd P, Lu¨scher B. Intracellular mono-ADP-ribosylation in signaling and disease. Cells 2015;4(4):56995. [156] Kugel S, Sebastia´n C, Fitamant J, Ross KN, Saha SK, Jain E, et al. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell 2016;165(6):140115. [157] Thornton JE, Gregory RI. How does Lin28 let-7 control development and disease? Trends Cell Biol 2012;22(9):47482. [158] Zhang Y, Nie L, Xu K, Fu Y, Zhong J, Gu K, et al. SIRT6, a novel direct transcriptional target of FoxO3a, mediates colon cancer therapy. Theranostics 2019;9(8):2380. [159] Jason S, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016;143(17):305060. [160] Jochemsen AG, Shiloh Y. USP10: friend and foe. Cell 2010;140(3):30810. [161] Sebastia´n C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 2012;151(6):118599. [162] Zhang CS, Yu Y, Huang QX, Tang K. SIRT6 regulates the proliferation and apoptosis of hepatocellular carcinoma via the ERK1/2 signaling pathway. Mol Med Rep 2019;20(2):157582. [163] Feng XX, Luo J, Liu M, Yan W, Zhou ZZ, Xia YJ, et al. Sirtuin 6 promotes transforming growth factor-β1/H2O2/HOC l-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence. Cancer Sci 2015;106 (5):55966. [164] Bai L, Lin G, Sun L, Liu Y, Huang X, Cao C, et al. Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway. Oncotarget 2016;7(26):40377. [165] Fischer SM, Pavone A, Mikulec C, Langenbach R, Rundhaug JE. Cyclooxygenase-2 expression is critical for chronic UV-induced murine skin carcinogenesis. Mol Carcinogenesis: Published Cooperation Univ Tex MD Anderson Cancer Cent 2007;46(5):36371. [166] Ford E, Voit R, Liszt G, Magin C, Grummt I, Guarente L. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev 2006;20(9):107580. [167] Yuan X, Zhou Y, Casanova E, Chai M, Kiss E, Grone HJ, et al. Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis. Mol Cell 2005;19(1):7787. [168] Chen S, Seiler J, Santiago-Reichelt M, Felbel K, Grummt I, Voit R. Repression of RNA polymerase I upon stress is caused by inhibition of RNA-dependent deacetylation of PAF53 by SIRT7. Mol Cell 2013;52(3):30313. [169] Wu D, Li Y, Zhu KS, Wang H, Zhu W-G. Advances in cellular characterization of the sirtuin isoform, SIRT7. Front Endocrinol (Lausanne) 2018;9:652. [170] Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res 2008;102(6):70310. [171] Kim JK, Noh JH, Jung KH, Eun JW, Bae HJ, Kim MG, et al. Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology 2013;57(3):105567. [172] Tang X, Shi L, Xie N, Liu Z, Qian M, Meng F, et al. SIRT7 antagonizes TGF-β signaling and inhibits breast cancer metastasis. Nat Commun 2017;8(1):114. [173] Li W, Zhu D, Qin S. SIRT7 suppresses the epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis by promoting SMAD4 deacetylation. J Exp Clin Cancer Res 2018;37(1):148.

II. Sirtuins and cancer

174

9. The bifunctional roles of sirtuins and their therapeutic potential in cancer

[174] McGlynn LM, McCluney S, Jamieson NB, Thomson J, MacDonald AI, Oien K, et al. SIRT3 & SIRT7: potential novel biomarkers for determining outcome in pancreatic cancer patients. PLoS One 2015;10(6):e0131344. [175] Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 2012;487(7405):11418. [176] Manuyakorn A, Paulus R, Farrell J, Dawson NA, Tze S, Cheung-Lau G, et al. Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704. J Clin Oncol 2010;28(8):1358. [177] Seligson DB, Horvath S, McBrian MA, Mah V, Yu H, Tze S, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol 2009;174(5):161928. [178] Malik S, Villanova L, Tanaka S, Aonuma M, Roy N, Berber E, et al. SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors. Sci Rep 2015;5(1):19. [179] Xie D, Gore C, Liu J, Pong R-C, Mason R, Hao G, et al. Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis. Proc Natl Acad Sci 2010;107(6):248590. [180] Deng Z, Wang X, Long X, Liu W, Xiang C, Bao F, et al. Sirtuin 7 promotes colorectal carcinoma proliferation and invasion through the inhibition of E-cadherin. Exp Ther Med 2018;15(3):233342. [181] Wang H-L, Lu R-Q, Xie S-H, Zheng H, Wen X-M, Gao X, et al. SIRT7 exhibits oncogenic potential in human ovarian cancer cells. Asian Pac J Cancer Prev 2015;16(8):35737. [182] Yu H, Ye W, Wu J, Meng X, Liu R-y, Ying X, et al. Overexpression of sirt7 exhibits oncogenic property and serves as a prognostic factor in colorectal cancer. Clin Cancer Res 2014;20(13):343445. [183] Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D, et al. Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 2012;119(8):190414. [184] Tervo AJ, Kyrylenko S, Niskanen P, Salminen A, Leppanen J, Nyronen TH, et al. An in silico approach to discovering novel inhibitors of human sirtuin type 2. J Med Chem 2004;47(25):629298. [185] Hu J, He B, Bhargava S, Lin H. A fluorogenic assay for screening Sirt6 modulators. Org Biomol Chem 2013;11(32):521316. [186] Galli U, Mesenzani O, Coppo C, Sorba G, Canonico PL, Tron GC, et al. Identification of a sirtuin 3 inhibitor that displays selectivity over sirtuin 1 and 2. Eur J Med Chem 2012;55:5866. [187] Pi H, Xu S, Reiter RJ, Guo P, Zhang L, Li Y, et al. SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 2015;11(7):103751. [188] Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 2001;276(42):3883743. [189] Lara E, Mai A, Calvanese V, Altucci L, Lopez-Nieva P, Martinez-Chantar ML, et al. Salermide, a Sirtuin inhibitor with a strong cancerspecific proapoptotic effect. Oncogene 2009;28(6):78191. [190] Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S, et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res 2006;66(8):436877. [191] Solomon JM, Pasupuleti R, Xu L, McDonagh T, Curtis R, DiStefano PS, et al. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol 2006;26(1):28. [192] Zhang Q, Zeng SX, Zhang Y, Zhang Y, Ding D, Ye Q, et al. A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumor growth through activation of p53. EMBO Mol Med 2012;4(4):298312. [193] He B, Hu J, Zhang X, Lin H. Thiomyristoyl peptides as cell-permeable Sirt6 inhibitors. Org Biomol Chem 2014;12(38):7498502. [194] Schuetz A, Min J, Antoshenko T, Wang CL, Allali-Hassani A, Dong A, et al. Structural basis of inhibition of the human NAD 1 -dependent deacetylase SIRT5 by suramin. Structure 2007;15(3):37789. [195] Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 2008;13(5):45463. [196] Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, et al. Sirtuin 2 inhibitors rescue alpha-synucleinmediated toxicity in models of Parkinson’s disease. Science 2007;317(5837):51619. [197] Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, et al. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat Commun 2015;6:6263. [198] Hwang ES, Song SB. Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cell Mol Life Sci 2017;74(18):334762. [199] Adams J, Klaidman L. Sirtuins, nicotinamide and aging: a critical review. Lett Drug Des Discov 2007;4:448. [200] Guan X, Lin P, Knoll E, Chakrabarti R. Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies. PLoS One 2014;9(9):e107729. [201] Audrito V, Vaisitti T, Rossi D, Gottardi D, D’Arena G, Laurenti L, et al. Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Res 2011; 71(13):447383. [202] Jung-Hynes B, Nihal M, Zhong W, Ahmad N. Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? The J Biol Chem 2009;284(6):382332. [203] Yousafzai NA, Zhou Q, Xu W, Shi Q, Xu J, Feng L, et al. SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer. Cell Death Dis 2019;10(5):363. [204] Alvala M, Bhatnagar S, Ravi A, Jeankumar VU, Manjashetty TH, Yogeeswari P, et al. Novel acridinedione derivatives: design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies. Bioorg Med Chem Lett 2012;22(9):325660. [205] Suzuki T, Khan MN, Sawada H, Imai E, Itoh Y, Yamatsuta K, et al. Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors. J Med Chem 2012;55(12):576073. [206] Bedalov A, Gatbonton T, Irvine WP, Gottschling DE, Simon JA. Identification of a small molecule inhibitor of Sir2p. Proc Natl Acad Sci U S A 2001;98(26):1511318. [207] Bedalov A, Chowdhury S, Simon JA. Chapter Nine - Biology, chemistry, and pharmacology of sirtuins. In: Marmorstein R, editor. Methods in enzymology, vol. 574. Academic Press; 2016. p. 183211.

II. Sirtuins and cancer

References

175

[208] Neugebauer RC, Uchiechowska U, Meier R, Hruby H, Valkov V, Verdin E, et al. Structureactivity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode. J Med Chem 2008;51(5):120313. [209] Rotili D, Tarantino D, Carafa V, Paolini C, Schemies J, Jung M, et al. Benzodeazaoxaflavins as sirtuin inhibitors with antiproliferative properties in cancer stem cells. J Med Chem 2012;55(18):81937. [210] Wang J, Kim TH, Ahn MY, Lee J, Jung JH, Choi WS, et al. Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells. Int J Oncol 2012;41(3):11019. [211] Fong Y, Lin Y-C, Wu C-Y, Wang H-MD, Lin L-L, Chou HL, et al. The antiproliferative and apoptotic effects of sirtinol, a sirtuin inhibitor on human lung cancer cells by modulating Akt/β-catenin-Foxo3a axis. Sci World J 2014;2014:937051. [212] Kozako T, Aikawa A, Shoji T, Fujimoto T, Yoshimitsu M, Shirasawa S, et al. High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T-cell leukemia cells. Int J Cancer 2012;131(9):204455. [213] Hsu Y-F, Sheu J-R, Lin C-H, Yang D-S, Hsiao G, Ou G, et al. Trichostatin A and sirtinol suppressed survivin expression through AMPK and p38MAPK in HT29 colon cancer cells. Biochim Biophys Acta (BBA) - Gen Subj 2012;1820(2):10415. [214] Jin KL, Park J-Y, Noh EJ, Hoe KL, Lee JH, Kim J-H, et al. The effect of combined treatment with cisplatin and histone deacetylase inhibitors on HeLa cells. J Gynecol Oncol 2010;21(4):2628. [215] Kojima K, Ohhashi R, Fujita Y, Hamada N, Akao Y, Nozawa Y, et al. A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells. Biochem Biophys Res Commun 2008;373(3):4238. [216] Ma W, Zhao X, Wang K, Liu J, Huang G. Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance antitumor efficacy in non-small cell lung cancer. Cancer Biol Ther 2018;19(9):83546. [217] Portmann S, Fahrner R, Lechleiter A, Keogh A, Overney S, Laemmle A, et al. Antitumor effect of SIRT1 inhibition in human HCC Tumor Models In vitro and In vivo. Mol Cancer Ther 2013;12(4):499. [218] Kalle AM, Mallika A, Badiger J, Alinakhi, Talukdar P. Sachchidanand. inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells. Biochem Biophys Res Commun 2010;401(1):1319. [219] Kaushik NK, Kaushik N, Attri P, Kumar N, Kim CH, Verma AK, et al. Biomedical importance of indoles. Molecules 2013;18(6):662062. [220] Napper AD, Hixon J, McDonagh T, Keavey K, Pons J-F, Barker J, et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem 2005;48(25):804554. [221] Trapp J, Meier R, Hongwiset D, Kassack MU, Sippl W, Jung M. Structureactivity studies on suramin analogues as inhibitors of NAD 1 -dependent histone deacetylases (sirtuins). ChemMedChem. 2007;2(10):141931. [222] Zhang JG, Hong DF, Zhang CW, Sun XD, Wang ZF, Shi Y, et al. Sirtuin 1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive response to chemotherapy-induced stress. Cancer Sci 2014;105(4):44554. [223] Oon CE, Strell C, Yeong KY, Ostman A, Prakash J. SIRT1 inhibition in pancreatic cancer models: contrasting effects in vitro and in vivo. Eur J Pharmacol 2015;757:5967. [224] Singh S, Kumar PU, Thakur S, Kiran S, Sen B, Sharma S, et al. Expression/localization patterns of sirtuins (SIRT1, SIRT2, and SIRT7) during progression of cervical cancer and effects of sirtuin inhibitors on growth of cervical cancer cells. Tumor Biol 2015;36(8):615971. [225] Kim HW, Kim SA, Ahn SG. Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability. Oncol Rep 2016;35(1):23542. [226] Yoon YK, Ali MA, Wei AC, Choon TS, Shirazi AN, Parang K. Discovery of a potent and highly fluorescent sirtuin inhibitor. MedChemComm. 2015;6(10):185763. [227] Tan YJ, Lee YT, Petersen SH, Kaur G, Kono K, Tan SC, et al. BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of colorectal cancer cells to 5-fluorouracil. Therapeutic Adv Med Oncol 2019;11 1758835919878977. [228] Zhang Y, Au Q, Zhang M, Barber JR, Ng SC, Zhang B. Identification of a small molecule SIRT2 inhibitor with selective tumor cytotoxicity. Biochem Biophys Res Commun 2009;386(4):72933. [229] Suenkel B, Fischer F, Steegborn C. Inhibition of the human deacylase Sirtuin 5 by the indole GW5074. Bioorg Med Chem Lett 2013;23(1):1436. [230] Huber K, Schemies J, Uciechowska U, Wagner JM, Rumpf T, Lewrick F, et al. Novel 3-arylideneindolin-2-ones as inhibitors of NAD 1 dependent histone deacetylases (sirtuins). J Med Chem 2010;53(3):13836. [231] Hawse WF, Hoff KG, Fatkins DG, Daines A, Zubkova OV, Schramm VL, et al. Structural insights into intermediate steps in the Sir2 deacetylation reaction. Structure 2008;16(9):136877. [232] Kiviranta PH, Suuronen T, Walle´n EAA, Leppa¨nen J, Tervonen J, Kyrylenko S, et al. NE-thioacetyl-lysine-containing tri-, tetra-, and pentapeptides as SIRT1 and SIRT2 inhibitors. J Med Chem 2009;52(7):21536. [233] He B, Du J, Lin H. Thiosuccinyl peptides as Sirt5-specific inhibitors. J Am Chem Soc 2012;134(4):19225. [234] Mellini P, Kokkola T, Suuronen T, Salo HS, Tolvanen L, Mai A, et al. Screen of pseudopeptidic inhibitors of human sirtuins 13: two lead compounds with antiproliferative effects in cancer cells. J Med Chem 2013;56(17):668195. [235] Dai H, Sinclair DA, Ellis JL, Steegborn C. Sirtuin activators and inhibitors: promises, achievements, and challenges. Pharmacol Ther 2018;188:14054. [236] Marshall GM, Liu PY, Gherardi S, Scarlett CJ, Bedalov A, Xu N, et al. SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS Genet 2011;7(6):e1002135. [237] Ueno T, Endo S, Saito R, Hirose M, Hirai S, Suzuki H, et al. The sirtuin inhibitor tenovin-6 upregulates death receptor 5 and enhances cytotoxic effects of 5-fluorouracil and oxaliplatin in colon cancer cells. Oncol Res 2013;21(3):15564. [238] Dai W, Zhou J, Jin B, Pan J. Class III-specific HDAC inhibitor Tenovin-6 induces apoptosis, suppresses migration and eliminates cancer stem cells in uveal melanoma. Sci Rep 2016;6(1):22622. [239] Yuan H, He M, Cheng F, Bai R, da Silva SR, Aguiar RCT, et al. Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy. Oncotarget 2017;8(9):1491224. [240] Jin Y, Cao Q, Chen C, Du X, Jin B, Pan J. Tenovin-6-mediated inhibition of SIRT1/2 induces apoptosis in acute lymphoblastic leukemia (ALL) cells and eliminates ALL stem/progenitor cells. BMC Cancer 2015;15(1):226. [241] Hirai S, Endo S, Saito R, Hirose M, Ueno T, Suzuki H, et al. Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. PLoS One 2014;9(7):e102831.

II. Sirtuins and cancer

176

9. The bifunctional roles of sirtuins and their therapeutic potential in cancer

[242] Igase M, Fujiki N, Shibutani S, Sakai H, Noguchi S, Nemoto Y, et al. Tenovin-6 induces the SIRT-independent cell growth suppression and blocks autophagy flux in canine hemangiosarcoma cell lines. Exp Cell Res 2020;388(1):111810. [243] Lee BB, Kim Y, Kim D, Cho EY, Han J, Kim HK, et al. Metformin and tenovin-6 synergistically induces apoptosis through LKB1independent SIRT1 down-regulation in non-small cell lung cancer cells. J Cell Mol Med 2019;23(4):287289. [244] Li L, Wang L, Li L, Wang Z, Ho Y, McDonald T, et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 2012;21(2):26681. [245] McCarthy AR, Sachweh MCC, Higgins M, Campbell J, Drummond CJ, van Leeuwen IMM, et al. Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner. Mol Cancer Ther 2013;12(4):352. [246] Dorfinger K, Niederle B, Vierhapper H, Astrid W, Czernin S, Nowotny P, et al. Suramin and the human adrenocortex: results of experimental and clinical studies. Surgery 1991;110(6):11005. [247] Marchetti D, Reiland J, Erwin B, Roy M. Inhibition of heparanase activity and heparanase-induced angiogenesis by suramin analogues. Int J Cancer 2003;104(2):16774. [248] Li H, Li H, Qu H, Zhao M, Yuan B, Cao M, et al. Suramin inhibits cell proliferation in ovarian and cervical cancer by downregulating heparanase expression. Cancer Cell Int 2015;15:52. [249] Stein CA, LaRocca RV, Thomas R, McAtee N, Myers CE. Suramin: an anticancer drug with a unique mechanism of action. J Clin Oncol 1989;7(4):499508. [250] La Rocca RV, Stein CA, Danesi R, Jamis-Dow CA, Weiss GH, Myers CE. Suramin in adrenal cancer: modulation of steroid hormone production, cytotoxicity in vitro, and clinical antitumor effect. J Clin Endocrinol Metab 1990;71(2):497504. [251] Ord JJ, Streeter E, Jones A, Le Monnier K, Cranston D, Crew J, et al. Phase I trial of intravesical Suramin in recurrent superficial transitional cell bladder carcinoma. Br J Cancer 2005;92(12):21407. [252] He X, Nie H, Hong Y, Sheng C, Xia W, Ying W. SIRT2 activity is required for the survival of C6 glioma cells. Biochem Biophys Res Commun 2012;417(1):46872. [253] Park EY, Woo Y, Kim SJ, Kim DH, Lee EK, De U, et al. Anticancer effects of a new SIRT inhibitor, MHY2256, against human breast cancer MCF-7 cells via regulation of MDM2-p53 binding. Int J Biol Sci 2016;12(12):1555. [254] Carafa V, Nebbioso A, Cuomo F, Rotili D, Cobellis G, Bontempo P, et al. RIP1-HAT1-SIRT complex identification and targeting in treatment and prevention of cancer. Clin Cancer Res 2018;24(12):2886900. [255] Carafa V, Poziello A, Della Torre L, Giovannelli P, Di Donato M, Safadeh E, et al. Enzymatic and biological characterization of novel sirtuin modulators against cancer. Int J Mol Sci 2019;20(22):5654. [256] Choi G, Lee J, Ji JY, Woo J, Kang NS, Cho SY, et al. Discovery of a potent small molecule SIRT1/2 inhibitor with anticancer effects. Int J Oncol 2013;43(4):120511. [257] Latuasan HE, Berends W. On the origin of the toxicity of toxoflavin. Biochim Biophys Acta 1961;52(3):5028. [258] Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. The J Biol Chem 2005;280(17):1718795. [259] Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. The J Biol Chem 2010;285(11):834051. [260] Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 2005;280(17):1703845. [261] Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 2014;35(3):14654. [262] Albani D, Polito L, Signorini A, Forloni G. Neuroprotective properties of resveratrol in different neurodegenerative disorders. BioFactors (Oxford, Engl) 2010;36(5):3706. [263] Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD 1 and sirtuin-activating compounds. Nat Rev Mol Cell Biol 2016;17(11):67990. [264] Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425(6954):1916. [265] Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science (New York, NY) 2013;339(6124):121619. [266] Polito L, Biella G, Albani D. Chapter 8 - Sirtuin modulation as novel neuroprotective strategy for Alzheimer’s disease. In: Gozes I, editor. Neuroprotection in Alzheimer’s disease. Academic Press; 2017. p. 14973. [267] Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007;450(7170):71216. [268] Bemis JE, Vu CB, Xie R, Nunes JJ, Ng PY, Disch JS, et al. Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators. Bioorg Med Chem Lett 2009;19(8):23503. [269] Villalba JM, Alcaı´n FJ. Sirtuin activators and inhibitors. BioFactors (Oxford, Engl) 2012;38(5):34959. [270] Balcerczyk A, Pirola L. Therapeutic potential of activators and inhibitors of sirtuins. BioFactors 2010;36(5):38393. [271] Monograph R. Resveratrol. Monogr. Altern Med Rev 2010;15:1528. [272] Delmas D, Lanc¸on A, Colin D, Jannin B, Latruffe N. Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer. Curr Drug Targets 2006;7(4):42342. [273] Alcaı´n FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Pat 2009;19(4):40314. [274] Suzuki K, Hayashi R, Ichikawa T, Imanishi S, Yamada T, Inomata M, et al. SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice. Oncol Rep 2012;27(6):172632. [275] Scuto A, Kirschbaum M, Buettner R, Kujawski M, Cermak JM, Atadja P, et al. SIRT1 activation enhances HDAC inhibition-mediated upregulation of GADD45G by repressing the binding of NF-κB/STAT3 complex to its promoter in malignant lymphoid cells. Cell Death Dis 2013;4(5):e635. [276] Raffaghello L, Longo V. Metabolic alterations at the crossroad of aging and oncogenesis. Int Rev Cell Mol Biol 2017;332:142.

II. Sirtuins and cancer

References

177

[277] Li G, Rivas P, Bedolla R, Thapa D, Reddick RL, Ghosh R, et al. Dietary resveratrol prevents development of high-grade prostatic intraepithelial neoplastic lesions: involvement of SIRT1/S6K axis. Cancer Prev Res 2013;6(1):27. [278] Chao S-C, Chen Y-J, Huang K-H, Kuo K-L, Yang T-H, Huang K-Y, et al. Induction of sirtuin-1 signaling by resveratrol induces human chondrosarcoma cell apoptosis and exhibits antitumor activity. Sci Rep 2017;7(1):3180. [279] Sun L, Li H, Chen J, Dehennaut V, Zhao Y, Yang Y, et al. A SUMOylation-dependent pathway regulates SIRT1 transcription and lung cancer metastasis. JNCI: J Natl Cancer Inst 2013;105(12):88798. [280] Sun L, Li H, Chen J, Iwasaki Y, Kubota T, Matsuoka M, et al. PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells. J Cell Sci 2013;126(17):3939. [281] Li Y-R, Li S, Lin C-C. Effect of resveratrol and pterostilbene on aging and longevity. BioFactors 2017;44(1):6982. [282] Sonnemann J, Kahl M, Siranjeevi P, Blumrich A, Blu¨mel L, Becker S, et al. Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing’s sarcoma cells: resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity. J Cancer Res Clin Oncol 2015;142(1):1726. [283] Chauhan D, Bandi M, Singh AV, Ray A, Raje N, Richardson P, et al. Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells. Br J Haematol 2011;155(5):58898. [284] Lahusen TJ, Deng CX. SRT1720 induces lysosomal-dependent cell death of breast cancer cells. Mol Cancer Ther 2015;14(1):18392. [285] Chini CCS, Espindola-Netto JM, Mondal G, Guerrico AMG, Nin V, Escande C, et al. SIRT1-activating compounds (STAC) negatively regulate pancreatic cancer cell growth and viability through a SIRT1 lysosomal-dependent pathway. Clin Cancer Res 2016; 22(10):2496507. [286] You W, Rotili D, Li TM, Kambach C, Meleshin M, Schutkowski M, et al. Structural basis of sirtuin 6 activation by synthetic small molecules. Angew Chem Int Ed 2017;56(4):100711. [287] Iachettini S, Trisciuoglio D, Rotili D, Lucidi A, Salvati E, Zizza P, et al. Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells. Cell Death Dis 2018;9(10):112. [288] Huang Z, Zhao J, Deng W, Chen Y, Shang J, Song K, et al. Identification of a cellularly active SIRT6 allosteric activator. Nat Chem Biol 2018;14(12):111826.

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C H A P T E R

10 Sirtuins and next generation hallmarks of cancer: cellular energetics and tumor promoting inflammation Robert Kleszcz and Wanda Baer-Dubowska ´ Poland Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, O U T L I N E 10.3.1 SIRT3 10.3.2 SIRT4 10.3.3 SIRT5

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10.1 Introduction: an overview of sirtuins involvement in inflammation and cancer metabolism The activities of mammalian sirtuins (SIRTs) depend on NAD1, as a cosubstrate for their histone deacetylase activity. In addition to its role as a cofactor in many enzymes, NAD1, regulates key metabolic processes involved in energy production and usage. Therefore SIRTs along with NAD1, play a critical role in guarding cellular homeostasis by sensing bioenergy needs and restoring it during stress response. Inflammation is the immune system’s response to different harmful stimuli and defends against cellular stress. However, uncontrolled acute inflammation may become chronic, contributing to a variety of diseases including cancer. Receptor activation by detrimental stimuli triggers intracellular signaling pathways such as the mitogen-activated protein-kinase (MAPK), nuclear factor kappa-B (NF-κB), activator protein 1 (AP-1), Janus kinase (JAK)-signal transducer, and activation of transcription (STAT) pathways [1 4]. Sirtuins, such as SIRT1, known to be a major metabolic regulator, epigenetically reprogram inflammation by altering histones and transcription factors, including NF-κB and AP-1 [5,6]. Inflammation links the immune, metabolic, and mitochondrial bioenergy pathways and SIRTs seem to be important modulators of these networks. Moreover, the inflammation connection with metabolism might be an important contributor to the development of cancer. One of the most intriguing features of cancer cells is the appearance of aerobic glycolysis, known as the Warburg effect. This phenomenon, which was first observed by Otto Warburg in the 1920s, was initially thought

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to be an adaptation to hypoxic conditions, but later studies showed that the mutations that lead to tumorigenesis also cause aerobic glycolysis by upregulating the expression of glycolytic genes at the transcriptional level [7]. It is now widely accepted that the Warburg effect is one of the key features of tumorigenesis [8]. It not only promotes rapid uncontrolled proliferation, but also confers invasive properties. The proposed mechanisms that underlie the Warburg effect include: (1) mitochondrial uncoupling, which can promote aerobic glycolysis in the absence of permanent and transmissible alterations to the oxidative capacity of cells; and (2) aerobic glycolysis, representing a shift to the oxidative metabolism of nonglucose carbon sources, particularly glutamine, an amino acid that is ultimately converted to α-ketoglutarate in the mitochondria in order to enter the citric acid cycle (CAC). Moreover, alterations in the glycolytic pathway itself may be equally or even more important. For example it was suggested that pyruvate kinase M2 (PKM2) or hexokinase 2 (HK2) might be the key mediators of aerobic glycolysis and promote tumor growth at least in certain types of tumors [9,10]. Epigenetic alterations, both on DNA and chromatin level in which SIRTs might play a particularly important role, seem to be equally important in glucose metabolism in cancer cells [11]. It has been shown that the loss of SIRT6 promotes cell glycolytic production toward lactate production, even in aerobic conditions [12]. This observation suggested that the lack of SIRT6 might provide a growth advantage for tumor cells. Additionally, it seems that promoter methylation of genes encoding enzymes affecting glycolysis may interfere with the same signaling molecules, namely NF-κB and hypoxia-inducible factor HIF1α [13]. Thus aerobic glycolysis in cancer cells and inflammation might be linked through epigenetic modulators of those transcription factors. In this regard multiple studies have showed that sirtuins, such as SIRT1 and SIRT2, limit inflammation. SIRT1 directly impacts inflammation by deacetylating and inactivating the p65 subunit of NF-κB, reducing the expression of NF-κB-dependent proinflammatory genes [14], as well as indirectly among the others via inhibition of the NLRP3 inflammasome activated by mitochondrial damage and reactive oxygen species (ROS) production [15]. Moreover, in macrophages activated by Lipopolysaccharide (LPS), the switch from oxidative phosphorylation to glycolysis occurs. As a result increased levels of intermediates of glycolysis and the pentose phosphate pathway (PPP) can be observed. This metabolic shift directly influences the inflammatory state of the cell [16]. It is likely that the increase in glycolysis allows for a rapid increase in adenosine triphosphate (ATP) production since, although less productive in terms of ATP synthesis than the CAC, glycolysis can be strongly induced [17]. This allows the macrophages to persist during the host defense response. The increase in the PPP allows for the production of intermediates for biosynthesis, such as purines and pyrimidines. The increased aerobic glycolysis and downregulation of the CAC refer to the Warburg effect observed in cancer cells. Interestingly, antiinflammatory M2 macrophages have decreased glycolysis and utilize oxidative metabolism. Therefore a movement toward high glycolysis might be indicative of inflammatory cells, whereas a shift toward oxidative phosphorylation is a hallmark of antiinflammatory cells. In turn, inflammatory cells promote cancer development sustained by aerobic glycolysis [15]. The above facts clearly point out the involvement of SIRTs in cancer metabolism and inflammation. As ROS formation is a key element of inflammatory defense, the SIRTs requirement for NAD1 further supports their function also in redox sensing as one of the mechanisms linking cancer and inflammation. In the next sections the role of specific sirtuins in the processes linking cancer metabolism, oxidative stress, and inflammation will be reviewed, taking into consideration their varied subcellular location.

10.2 Nuclear and cytosolic sirtuins involvement in metabolism of cancer and inflammatory cells 10.2.1 SIRT1 Overwhelming evidence suggests that SIRT1 senses nutritional availability and passes this information to proteins that control fuel utilization and energy adaptation. SIRT1 binds to and deacetylates a number of important transcription factors, such as peroxisome proliferator activated receptor gamma (PPARγ), PPARα, PPAR gamma coactivator 1 alpha (PGC-1α), and forkhead box, subgroup O (FOXO) family of transcription factors to drive metabolic responses such as gluconeogenesis and fatty acids oxidation [18]. In this regard deacetylation of FOXO1 increases the expression of the gene encoding adipose triacylglycerol lipase (ATGL), which is involved in adipose lipids mobilization [19,20]. In turn, deacetylation of PPARγ suppresses adipogenesis in concert with decreased cholesterol and lipids production resulting from SIRT1 modification of sterol regulatory element-binding protein 1 (SREBP1) [21]. Deacetylating of PGC-1α causes a shift in mitochondrial substrate usage promoting fatty acids oxidation and preserving glucose. This switch is supported by increased transcription of mitochondrial fatty acid

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oxidation and oxidative phosphorylation genes suggesting that SIRT1 may couple fatty acid oxidation with ATP production [18,22]. Downregulation of glycolysis by SIRT1 may result on one hand from deacetylation of HIF1α, and phosphoglycerate mutase 1 (PGAM1) on the other. The gene encoding the latter is the only glycolytic enzyme which is not controlled by HIF1α [23,24]. Aerobic glycolysis and limited mitochondrial activity are the hallmarks of cancer cells as well as inflammatory cells, which in addition promote cancer development that is sustained by aerobic glycolysis. The SIRT1-induced metabolic switch from glucose to fatty acid oxidation may be considered as one of the mechanisms of the calorie restriction (CR) protective effect against cancer [25]. In turn CR induces SIRT1 upregulation [26]. Besides metabolic effects, SIRT1 protects against oxidative stress and inflammation via the upregulation of FOXO3-dependent antioxidant enzymes, for example, catalase and interaction with RelA/p65 subunit of NF-κB leading to its downregulation [14,27 29]. Overall, SIRT1’s influence on bioenergetic metabolism can counteract the aerobic glycolysis both in cancer cells and inflammatory cells and thus limit their survival.

10.2.2 SIRT2 SIRT2 is basically a cytoplasmic enzyme, but also can be found in the nucleus and inner mitochondrial membrane [30,31]. It was suggested that the major function of SIRT2 in cooperation with SIRT1 is induction of mitotic arrest in critically damaged cells, allowing them to proceed to apoptosis. Therefore the inhibition of SIRT2 may predispose cells to uncontrolled growth [18]. SIRT2, similarly to SIRT1, is involved in the regulation of glucose metabolism affecting the expression and/or activity of the key enzymes of its catabolic pathways. In this regard PGAM, a glycolytic enzyme, commonly upregulated in several cancers, is deacetylated by SIRT2 at lysines 100/106/113/138 in its central region. Overexpression of SIRT2 or mutations at gene sites encoding the acetylatable lysines of PGAM attenuates cancer cell proliferation with a concomitant decrease in PGAM activity [32]. The isoform of pyruvate kinase PKM2 was also shown to be a critical target of SIRT2 that is implicated in cancer. When PKM2 is in its active tetramer state pyruvate is directed into mitochondria, ultimately providing ATP via oxidative phosphorylation [33]. In contrast, when PKM2 dissociates a decrease in enzymatic activity, it is observed that it blocks pyruvate production. The study of Park et al. showed that acetylation reduced PKM2 activity by preventing the formation of the active tetrameric form of enzyme. Overexpression of deacetylated PKM2 mutant in SIRT2-deficient mammary tumor cells altered glucose metabolism and inhibited malignant growth. Therefore the loss of SIRT2 in cancer reprograms glycolytic metabolism via PKM2 toward enhanced aerobic glycolysis [34]. A more recent study using primed pluripotent stem cells showed that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase, and enolase. Moreover, knockdown of SIRT2 in human fibroblasts resulted in significantly decreased oxidative phosphorylation and increased glycolysis [35]. On the other hand, the combination of SIRT2 inhibitor with dehydrogenase kinase inhibitor efficiently activated pyruvate dehydrogenase E1 component (PDHA1), and shifted the metabolism of nonsmall cell lung cancer (NSCLC) to oxidative phosphorylation, enhancement of ROS generation, and activation of AMP-activated protein kinase (AMPK) signaling [36]. The PPP plays a pivotal role in meeting the anabolic demands for cancer cells. SIRT2 deacetylates the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) and promotes NADPH production. It was shown that activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukemia cells. Moreover, SIRT2 is overexpressed in clinical acute myeloid leukemia (AML), while G6PD acetylation is downregulated and its activity is increased compared to that of normal cells [37]. Similarly to SIRT1, SIRT2 affects the lipid metabolism, blocking adipogenesis through the repression of transcriptional activity of PPARγ [38]. Recently, the involvement of SIRT2 in mitochondrial metabolism was described [31]. In this regard, acetylation of several metabolic mitochondrial proteins was found to be altered in SIRT2-deficient mice resulting in increased oxidative stress and decreased ATP levels in some tissues. In summary, SIRT2 involvement in energy metabolism in cancer cells rather facilitates their survival. However, its effects on cell cycle and subsequent induction of apoptosis indicates that increased activity of SIRT2 in certain cancers could be beneficial.

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10.2.3 SIRT6 SIRT6 is a nuclear sirtuin which has both ADP-ribosyltransferase and deacetylase activity preferentially acting on histone H3K9 and H3K56 [39]. SIRT6 plays various roles in metabolism, stress resistance, and life span. SIRT6 appears to function as a corepressor of the transcription factor HIF1α by deacetylating H3K9 at HIF1α target gene promoters. SIRT6-deficient cells exhibit increased HIF1α activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration [12,29]. This sirtuin is described as a master regulator of glucose metabolism and tumor suppressor that regulates aerobic glycolysis in cancer cells. Lack of this chromatin factor leads to tumor formation even in nontransformed cells. Notably, inhibition of glycolysis in SIRT6-deficient cells completely rescues their tumorigenic potential, suggesting that enhanced glycolysis is the driving force for tumorigenesis in these cells [40]. Early studies of Zhong et al. demonstrated that SIRT6 regulates glucose homeostasis via inhibiting multiple glycolytic genes, including the glucose transporter GLUT1, by promoter binding and histone deacetylation. This allows mitochondrial oxidative phosphorylation, but not glycolysis, to generate efficient ATP production. Consequently, the loss of SIRT6 increases glycolysis and diminishes mitochondrial respiration [12]. Evidence exists that SIRT6 may exert this activity by interacting not only with HIF1α, but also MYC transcription factor, acting as its corepressor. SIRT6 deacetylates H3K56 of MYC target genes. Although knocking out SIRT6 may lead to neoplastic transformation in cell lines, the interaction with MYC is rather necessary to exert this effect in vivo indicating a key role of this sirtuin in controlling cancer cell proliferation by corepressing MYC transcriptional activity [40]. However, the loss of SIRT6 corepressor activity engages also glutamine metabolism and ribosomal biogenesis independent of mutations in growth factor signaling pathways. Activation of each of these distinct metabolic components is necessary for tumorigenesis, and together, this metabolic reprograming is sufficient to transform cells [41]. The observation that tumors showing lack of SIRT6 activity grow to be bigger and more aggressive than SIRT6-expressing tumors further adds to the evidence for the crucial importance of SIRT6-mediated regulation of glycolysis and cell proliferation in tumorigenesis. Therefore the tumor suppressor role for SIRT6 is strictly dependent on its ability to repress aerobic glycolysis and maintaining glucose homeostasis is well documented. It was suggested that the latter is exerted by at least three different mechanisms: (1) inhibiting the activity of HIF1α, a transcription factor that drives glycolysis and simultaneously inhibits oxidative phosphorylation [12]; (2) attenuating insulin IGF-1-like signaling pathway and glucose uptake by reducing JUN transcriptional activity [42,43]; and (3) inhibiting hepatic gluconeogenesis by promoting acetylation of the transcription factor PGC-1α [44]. SIRT6 deacetylates the histone acetyltransferase GCN5, which in turn acetylates and activates the transcriptional regulator PGC-1α, reducing de novo production of glucose, that is, gluconeogenesis in the liver [45]. SIRT6 also affects cholesterol synthesis repressing the transcription of SREBP1/SREBP2 and that of their target genes as well as their activation by inhibition of SREBP1/SREBP2 cleavage to their active forms. On the mechanistic level, SIRT6 is recruited by FOXO3 to the Srebp2 gene promoter where SIRT6 deacetylates histone H3 at lysines 9 and 56, thereby promoting a repressive chromatin state. Remarkably, SIRT6 or FOXO3 overexpression improves hypercholesterolemia in diet-induced or genetically obese mice [46,47]. Cholesterol plays an important role in cancer development. Both clinical and experimental studies have found that hypercholesterolemia and a high-fat high-cholesterol diet can affect cancer development. External cholesterol can directly activate the oncogenic Hedgehog pathway, and internal cholesterol can induce mTORC1 signaling. Cholesterol is a key component of lipid rafts, which are subdomains of the plasma membrane that contain high concentrations of cholesterol and glycosphingolipids [48]. Lipid rafts are the major platforms for signaling regulation in cancer, and chelating membrane cholesterol is an effective anticancer strategy that disrupts the functions of lipid rafts. Cholesterol metabolism is often reprogrammed in cancer cells [49]. Thus reducing cholesterol synthesis as a result of SIRT6 interference with its regulating elements/proteins indicates its additional role in cancer suppression. Besides the mediation of HIF1α signaling, SIRT6 also interacts with RelA subunit of NF-κB and deacetylates histone H3K9 at NF-κB target gene promoters, which leads to their repression. The disruption of the SIRT6 gene results in the hyperactivation of NF-κB signaling [50]. Min et al. have shown using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-κB activation [51]. Moreover, in human dysplastic liver nodules, but not in malignant tumors, a specific expression pattern with increased c-Jun-survivin and attenuated c-Fos and SIRT6 levels was identified. These observations indicate the existence of a regulatory

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FIGURE 10.1 SIRT6’s interaction with transcription factors HIF1α, MYC, and NF-κB. SIRT6 suppresses glutaminolysis through interaction with MYC. Glycolysis is downregulated as a result of its interaction with HIF1α and MYC. Decreased oxidative stress results from reduced NF-κB activity and normalized energy metabolism (HIF1α and MYC). In this way SIRT6 may lower the risk of chronic inflammation and transformation of malignant cells.

network connecting stress response, inflammation, and histone modification in liver tumor initiation, which could be targeted to prevent liver tumorigenesis [29]. SIRT6’s interaction with HIF1α, MYC, and NF-κB target genes importantly affects cellular energy metabolism, oxidative stress, and subsequent also (cancer-related) inflammation (Fig. 10.1). Although SIRT6 is considered to be a tumor suppressor it may also act as a tumor promoter. High SIRT6 levels have been reported in breast cancer, pancreatic cancer, and prostate cancer, and are associated with drug resistance and poor prognosis [29]. High SIRT6 levels promote cellular proliferation through deacetylation of the cell cycle control proteins FOXO3a and p53, and increase IL-8- and TNF-mediated inflammatory responses, angiogenesis, and tumor metastasis in part through activation of the Ca21 channel TRPM2 [45]. Moreover, in BCPAP papillary thyroid cancer cells upregulated SIRT6, thus promoting the aerobic glycolysis through upregulation of GLUT1, HK2, and GAPDH genes, and increased ROS production. Treatment with ROS scavengers normalized the expression of these genes as well as glucose uptake and lactate production, suggesting that SIRT6 promoted the Warburg effect of papillary thyroid cancer cells via the upregulation of ROS. Thus the inhibition of ROS in SIRT6-upregulated cells could rescue activation of the Warburg effect [52]. As ROS production is essential for killing pathogens, it is also central to the progression of many inflammatory diseases, including cancer. Thus increased ROS production in cancer cells with upregulated SIRT6, along with the other events, for example, development of angiogenesis, contributes to SIRT6’s tumor-promoting activity.

10.2.4 SIRT7 SIRT7 is arguably the least studied of the mammalian sirtuins and the only known lysine deacetylase selectively removing acetylation from Lys 18 at histone 3. This specific histone mark is particularly associated with highly malignant cancer and poor prognosis [53]. SIRT7 was reported to activate transcription of rRNA by RNA polymerase I through specific interaction of its subunit PAF53 with the transcription factor UBF, which allows the pre-rRNA processing [54,55]. Since rRNAs are essential elements of ribosomes, SIRT7 is involved in their biogenesis. This process, along with enhanced glycolysis and excessive PPP activity, fits the highly proliferative potential of cancer cells [56]. On the other hand, SIRT7 was described as a negative regulator of the hypoxia responsive pathway. SIRT7 overexpression decreased HIF1α and HIF2β protein levels, transcriptional activity, and target gene expression [57]. In this way SIRT7 indirectly can downregulate the aerobic glycolysis in cancer and/or inflammatory cells. Moreover, SIRT7 has been shown to suppress endoplasmic reticulum stress and prevent the development of fatty liver disease. Mechanistically, this effect was explained by a recent finding that SIRT7 maintains energy homeostasis by deacetylating GABPβ1, a central regulator of mitochondrial function. As deacetylation is required for GABPβ1 activity, SIRT72/2 mice displayed pathologies that resemble phenotypes of mitochondrial diseases, which include cancer. Energy starvation induces ubiquitin-independent degradation of SIRT7, which leads to

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attenuation of ribosome biogenesis and maintenance of cellular energy homeostasis [55]. This supports the widespread functions of SIRT7 in response to metabolic demands. Overall, this sirtuin may contribute to cancer metabolic phenotypes in different ways. That is why some authors have described SIRT7 as protein having seven faces [55].

10.3 Mitochondrial sirtuins Mitochondria generate high-energy phosphate bonds of ATP by an electrochemical proton gradient created by the transfer of electrons through a series of electron carriers embedded in the mitochondrial membrane. Transfer of electrons to molecular O2 is tightly controlled, and only 1% 2% of electrons that leaked out in this process react with O2 resulting in ROS, namely superoxide radical formation [58]. The main sites of superoxide radical production in the electron transport chain (ETC) are complex I and III [59,60]. Superoxide radicals generated by mitochondria react with manganese superoxide dismutase (MnSOD, SOD2) in the mitochondrial matrix to generate H2O2, which can cross the mitochondrial outer membrane to access cytosolic targets. This can lead to multiple functional outcomes such as activation of redox-sensitive transcription factors, including HIF1α, and NF-κB activation of proinflammatory cytokines and activation of inflammasomes. Therefore mitochondrial sirtuins activity may be directly or indirectly involved in mitochondrial-derived oxidative stress and subsequently chronic inflammation and cancer [61]. Mitochondrial sirtuins obviously do not target histone proteins but deacetylate or modify lysine residues in proteins important for processes occurring in this compartment, particularly those linked with the ETC.

10.3.1 SIRT3 SIRT3 is the best characterized mitochondrial sirtuin. Acting as a protein deacetylase, it regulates metabolism, respiration, and stress control in that cellular compartment [62]. SIRT3 may enhance the ATP production via oxidative phosphorylation by catalyzing the deacetylation of protein components of the ETC, including NDUFA9 (NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9), which is a member of complex I of the ETC [11,63], SDHA (succinate dehydrogenase subunit A) in complex II, and ATP synthase subunit β [64 66]. Moreover, it was shown that SIRT3 is involved in fatty acid oxidation, where it deacetylates long-chain acyl CoA dehydrogenase and upregulates its enzymatic activity along with activation of 3-hydroxy-3-methylglutaryl CoA synthase 2 involved in ketogenesis during fasting [67,68]. The quantitative acetyl-proteomic analysis applied to examine the function of resident deacetylase SIRT3 in mediating the CR response revealed that SIRT3 is a major regulator of the mitochondrial acetylome in response to CR [69]. Since CR is linked with beneficial effects on cancer and the way of its prevention, these findings provide an additional argument for the role of SIRT3 in the suppression of tumor growth [25]. SIRT3 also interacts with acetyl-CoA synthetase 2 and by deacetylation of lysine 642 increases the enzyme activity in both in vitro and in vivo systems [70,71]. SIRT3 may be involved in the redirection of pyruvate, a glycolysis end product, into the CAC by activation of PDH1 as a result of deacetylation of its lysine residues [72], which ultimately reduces cancer cells proliferation [73]. The most important function of SIRT3 in the context of ROS and inflammation is involvement in the regulation of ROS production, most probably through modulating SOD2 [74,75]. SIRT3-mediated deacetylation of Lys122 of SOD2 increases the enzyme activity and allows ROS scavenging [74]. SIRT3 also deacetylates Lys144 of mitochondrial isocitrate dehydrogenase IDH2, which uses NADP1 as a cofactor, producing the NADPH required for maintaining a reduced form of glutathione and self-maintaining active IDH2, which might be inactivated by oxidized glutathione [76]. SIRT3 deficiency leads to the overproduction of ROS and HIF1α stabilization by protection against proteasomal degradation and subsequent increased expression of its target genes, including those encoding glycolytic enzymes [77,78]. Recent studies indicate that SIRT3 may increase the expression of genes encoding antioxidant enzymes through the deacetylation of FOXO3 transcription factor [79,80]. Overall, SIRT3 is a key NAD1-dependent protein deacetylase in the mitochondria of mammalian cells, functioning to prevent cell transformation via regulation of mitochondrial metabolic homeostasis. However, SIRT3 is also found to express in some human tumors; its role in these SIRT3-expressing tumor cells needs to be elucidated [81].

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10.3.2 SIRT4 SIRT4 is a mitochondrial enzyme that was initially thought to be deprived deacetylating activity and to catalyze only an alternative reaction involving the transfer of ADP-ribose from NAD1 to the substrates [82]. Now it is known that SIRT4 deacetylates and inhibits malonyl-CoA decarboxylase (MCD), an enzyme that produces acetyl-CoA from malonyl-CoA. Malonyl-CoA provides the carbon skeleton for lipogenesis and also inhibits lipids oxidation [83,84]. More recently SIRT4 deacetylating activity has been shown to influence the stability of mitochondrial trifunctional protein α-subunit (MTPα). This protein subunit contains the long-chain hydratase 3-hydroxyacyl-CoA dehydrogenase and catalyzes the second and third steps of fatty acid oxidation [85,86]. SIRT4-mediated deacetylation of MTPα induces destabilization of the enzyme by promoting its ubiquitination and degradation. In this way, SIRT4 also functions to inhibit fatty acid oxidation in the liver [87]. Overall, SIRT4 is considered to be a regulator of lipid homeostasis and is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. Recently SIRT4 has emerged as an enzyme capable of removing diverse postranslational modifications (PTM) from its substrates, thereby modulating their functions. One such PTM is lipoylation, which is thought to be an exceedingly rare PTM. There are only four known lipoylated multicomponent enzymatic complexes in mammals: pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase complex, branched-chain α-ketoacid dehydrogenase complex, and the glycine cleavage system [87,88]. Lipoyl modifications are essential for the enzymatic activities of these complexes, but also for capturing and presenting substrate intermediates between the active sites of the multicomponent. It was found that SIRT4 interacts with subunits from all four lipoylated multicomponent enzymatic complexes, as well as biotin-dependent carboxylases in humans. SIRT4 was shown to remove lipoyl groups from the pyruvate dehydrogenase (PDH) subunit dihydrolipoyl transacetylase (DLAT). The lipoamidase activity of SIRT4 was confirmed in cell culture and in vivo in mice and indicated that removal of lipoylation inhibits the activity of PDH [87,89]. Therefore SIRT4 might be an important regulatory point between glycolysis and the CAC. SIRT4-catalyzed transfer of ADP-ribose from NAD1 to the substrates might be involved in glutamine metabolism leading to the inhibition of glutamate dehydrogenase (GDH). This enzyme converts glutamate into α-ketoglutarate [82] and along with glutaminase 1 (GLS1), which transforms glutamine to glutamate, it serves to replenish the CAC [90]. The flow of amino acids metabolites into the CAC is limited by the inactivation of GDH. This effect can be reversed, because GDH is activated by the mammalian target of rapamycin complex 1 (mTORC1) via repression of SIRT4 and thereby increases glutamine metabolism [91]. Glutamine metabolism plays an important role in the proliferation of cancer cells by replenishing the CAC intermediates to support increased growth and by producing ammonia, which neutralizes the acidic metabolites frequently produced as a result of increased glycolysis in cancer cells. Therefore SIRT4 inhibition of glutamine metabolism via repression of GDH activity is thought to contribute to its function as a tumor suppressor [87]. It was found that DNA damage induced a massive increase in SIRT4 expression, which triggered a shutdown of glutamine metabolism that was sufficient to arrest progression of the cell cycle [92]. Thus this mechanism may prevent tumor development through a checkpoint which combines a significant decrease in glutamine use with the induction of cell cycle arrest, thus allowing cells to repair the damage [93,94]. SIRT4 displays features of a tumor suppressor in experimental systems, and its expression is reduced in a substantial number of human cancers [91,93]. Thus SIRT4 may exert its tumor suppressor function by both repressing glutamine metabolism and promoting genome stability. However, SIRT4 is upregulated in several tumors, can induce cellular stresses that are associated with tumorigenesis, and can prepare tumor cells to gain selective advantages. Therefore in several tumors and clinical cases, SIRT4 may play an oncogenic role, which requires further studies for confirmation [95].

10.3.3 SIRT5 SIRT5 in contrast to the other sirtuins shows low, although detectable, deacetylase activity. The only known physiological substrate with regard to its deacetylating activity is carbamoylphosphate synthetase 1 (CPS1). This enzyme catalyzes the first and rate-limiting step of the urea cycle. SIRT5 deacetylates and activates CPS1, and thus plays an important role in the regulation of the urea cycle [96]. However, SIRT5 enzymatic activity is unique compared with that of other sirtuin proteins. The analysis of the crystal structure of SIRT5 bound to a substrate peptide revealed that SIRT5 possesses a larger binding cavity compared with other sirtuins, with three unique active site amino acid residues, Ala86, Tyr102, and Arg105. It was established that SIRT5 efficiently removes acidic acyl groups—succinyl, malonyl, and glutaryl moieties—from lysine residues [97]. Therefore SIRT5 targets hundreds of

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protein substrates, particularly those localized in mitochondrial matrix, with many involved in cellular metabolism including the CAC, urea cycle, and fatty acids oxidation, but also was shown to act in cytosol affecting multiple glycolytic enzymes [98 102]. In general, SIRT5’s involvement in cell metabolism, particularly concerning glucose, favors metabolic reprogramming and a tumor-promoting cellular metabolism [97]. In this regard the lack of SIRT5 causes downregulation of glucose transporter GLUT1, for example, in NSCLC H1299 cells [103]. SIRT5 was shown to demalonylate GAPDH, which catalyzes the conversion of glyceraldehyde 3-phosphate to glycerate 1,3-bisphosphate in glycolysis, resulting in increased GAPDH and elevated glycolytic flux [97,98]. SIRT5-dependent inhibition of PKM2 in A549 and 293T NSCLC cells as result of Lys498 desuccinylation led to reduced glycolytic flux, reduced mitochondrial respiration, and enhancement of cell proliferation [104]. On the other hand it was also shown that Lys311 desuccinylation enhanced PKM2 activity [105]. In fact, both actions may positively influence the PPP, because disrupted flux of metabolites via PKM2 lower activity, as well as PKM2 in a low-active dimer state, enables the increase of the PPP glucose-6-phosphate entry. A conversion into 6-phosphogluconolactone is conducted by G6PD, which is activated by deglutarylation via SIRT5 [106]. Thus accelerated PPP produces elements for macromolecules synthesis and improves antioxidant defense. SIRT5 has been shown to repress the activity of PDH complex E1α subunit by desuccinylation [99]. Moreover, SIRT5 catalyzed deacetylation of STAT3. This cytosolic transcription factor undergoes mitochondrial translocation and subsequently regulates mitochondrial pyruvate metabolism. Deacetylation inhibits its function [107]. On the other side, SIRT5 deficiency correlates with lower lactate dehydrogenase A (LDHA) expression [103], so in SIRT5 active state pyruvate can be redirected to LDHA to produce lactate, a metabolic marker of the Warburg effect. Recently in colorectal cancer cells an interaction between lactate dehydrogenase B (LDHB) isoenzyme and SIRT5 was demonstrated. SIRT5 is a binding partner of LDHB and deacetylates Lys329 to promote LDHB enzymatic activity, followed by increased autophagy and accelerated growth of colorectal cancer cells, but also cancer progression in patients [108]. The SIRT5-mediatied regulation of the CAC and subsequently the ETC and oxidative phosphorylation is not unidirectional. In 293T cells SIRT5 the desuccinylation of SDHA, which is also the complex II of the ETC was described. Lack of succinylation disrupts conversion of succinate to fumarate, coupled with reduction of NAD1 to NADH and the generation of ubiquinol from ubiquinone [99]. However, it was also shown that SIRT5 electrostatically binds to cardiolipin and desuccinylates inner mitochondrial membrane proteins, including all four ETC complexes and ATP synthase, and finally promotes cellular respiration [109]. SIRT5 also interacts with complex I subunit NDUFA4 and cytochrome C [105]. SIRT5 involvement in the CAC is related mainly to its effect on IDH2 activation [106]. In mitochondria exist two isoforms of IDH, both transforming isocitrate to α-ketoglutarate. One, IDH3 uses NAD1 as an electron acceptor and acts in the CAC by irreversible decarboxylation of isocitrate to yield α-ketoglutarate, while IDH2 catalyzes reversible decarboxylation of isocitrate to α-ketoglutarate while reducing NADP1 to NADPH or acting in the reductive carboxylation reaction to convert α-ketoglutarate to isocitrate while oxidizing NADPH to NADP1 [76]. The importance of IDH2 activation is bifunctional. Mutations in IDH1 (cytosolic form of IDH) and IDH2 have been identified as driving events, for example, in gliomas and AML [110]. These heterozygous mutations cause the production of the oncometabolite 2-hydroxyglutarate (2-HG), which inhibits α-ketoglutarate-dependent dioxygenases related to DNA and histone demethylation, in turn leading to protumorigenic epigenetic dysregulation [97]. In addition, the increase of NADPH production by IDH2 enhances oxidative stress defense, because NADPH is necessary in the regeneration of glutathione (GSH) from its oxidized (GSSG) form by glutathione reductase [111]. SIRT5 tends to protect cancer cells from ROS also via the desuccinylation and activation of Cu/Zn superoxide dismutase (SOD1) [112] and G6PD, a key enzyme of the PPP [106]. In NSCLC cells induced overexpression of SIRT5 was positively correlated with expression of the Nrf2 gene, thus the expression of Nrf2-target genes involved in cellular redox homeostasis was also improved [113]. Antioxidant effects of SIRT5 and its further influence on cytochrome C related with intrinsic apoptotic cascade or antiapoptotic B cell lymphoma-XL (BCL-XL) protein suggests SIRT5 engagement in cancer cells’ evasion of apoptotic death [30,97,105]. Fatty acids β-oxidation is a four-step process of fatty acid breakdown into acetyl-CoA. For very long fatty acylCoA (VLCFA) substrates, very-long-chain acyl-CoA dehydrogenase (VLCAD) converts these intermediates to enoyl-CoA, and further enoyl-CoA hydratase (ECHA, a subunit of the mitochondrial trifunctional complex) catalyzes conversion of enoyl-CoA to ketoacyl- and acetyl-CoA to break down fatty acids for energy [97]. Two mitochondrial sirtuins, SIRT3 and SIRT5, together promote fatty acids β-oxidation via the deacetylation of VLCAD, thereby promoting its mitochondrial membrane localization, increasing its activity and enhancing conversion of acyl-CoA to enoyl-CoA [97,105,114]. However, SIRT5, similarly to SIRT3, may stimulate the ketone body production by the desuccinylation of 3-hydroxy-3-methylglutaryl CoA synthase 2 [101].

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Influence on nitrogen metabolism is also related to the wide metabolic function of SIRT5. As previously mentioned, SIRT5 supports ammonia detoxification via the stimulation of CPS1 activity and conversion of ammonia to carbamoyl phosphate to initiate the formation of urea for excretion [97]. But SIRT5 may also reduce the production of ammonia in the glutaminolysis pathway. The influence on CPS1 is limited to liver and partly kidney. However, in human breast cancer cell lines MDA-MB-231 and mouse myoblast C2C12 overexpressing SIRT5 ammonia production by repressed glutaminase was reduced [115]. To sum up, SIRT5 regulates several aspects of glucose metabolism across multiple subcellular compartments. It reprograms cells to use glucose rather than producing lactate and stimulates the PPP to produce biomolecules and NADPH. Furthermore, it promotes fatty acids β-oxidation together with the production of ketone bodies. SIRT5 protects cells from oxidative stress and ammonia toxicity by interaction with, for example, glutaminolysis or activity of CPS1 and SOD1. In some cancer tissues with an IDH2 mutation SIRT5 can contribute to the production of the novel oncometabolite 2-HG, which modulates epigenetic changes for tumor survival. Negative regulation of the ETC complex II might potentially affect ATP production, but SIRT5 deficiency in HEK293T leads to suppression of mitochondrial NADH oxidation and inhibition of ATP synthase activity, and subsequently activates AMPK [116]. Thus SIRT5 promotes metabolic reorganization that favors tumor promotion. Nowadays, little is known on its impact on innate immune defenses and inflammation. A recent study using SIRT5 knockout mice showed that SIRT5 deficiency does not affect immune cell development, cytokine production, and proliferation by macrophages and splenocytes exposed to microbial and immunological stimuli [117]. However, SIRT5-dependent inhibition of PKM2 may potentially affect inflammatory cells. To summarize the general roles of sirtuins in cellular metabolism, Fig. 10.2 presents the tendency of action of particular sirtuins according to glycolysis, fatty acids metabolism, and glutaminolysis.

FIGURE 10.2 The effect of sirtuins in cellular energy metabolism. Due to varied tissue specificity, the dominant effect is presented. CAC, Citric acid cycle; ETC, electron transport chain.

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10.4 Sirtuins indeed link metabolism, inflammation, and cancer? The causal relationship between inflammation, innate immunity, and cancer is now widely accepted. However, many of the molecular and cellular mechanisms mediating this relationship are not clear yet. Furthermore, tumor cells may take over key mechanisms by which inflammation interfaces with cancers to further host invasion [118]. In this regard angiogenesis, which is one of the hallmarks of cancer, is closely linked with inflammation [119]. Energy metabolic pathways have a direct influence on pro- and antiinflammatory responses in macrophages, which, in response to danger signals, reprogram the nutrient metabolic pathway toward aerobic glycolysis. Thus in both cancer cells and activated macrophages similar metabolic changes occur. SIRTs seem to be important regulators of these processes. However, as it was described in previous sections, SIRTs can function both as suppressors or tumor promoters depending on the specific form, tissue, and microenvironment. Moreover, an important part of SIRTs’ metabolic effects is related to cellular redox balance [28]. An imbalance in redox processes favors the creation of a proinflammatory microenvironment, suitable for cancer development [8]. The family of FOXO transcription factors controls expression of genes encoding proteins diminishing oxidative stress. Catalase and MnSOD are the two most important FOXO3a target genes related to the ROS defense and their expression is partly controlled by SIRT1, 2, and 3 [28,79,80,120]. SIRT5 can also protect cancer cells from oxidative stress by desuccinylation and activation of SOD1 [112]. Inversely, SIRT6-dependent deacetylation can suppress FOXO3a, thus impairing the ROS balance [121]. In view of mitochondrial localization, SIRT3, 4, and 5 mostly influence ROS production. Beyond promoting SOD2, SIRT3 and 5 augment IDH2 activity, resulting in enhancement of NADPH synthesis [76]. SIRT3 activity is particularly involved in the decrease of oxidative stress as the result of the normalization of cellular energetics. As previously mentioned, SIRT3 interacts with the ETC proteins, for example, NDUFA9 and SDHA, thus it may improve the electron flow through the ETC and in this way may protect against mitochondria-derived ROS. Excessive production of ammonia might be another stress-inducing event for cells. SIRT3 targets ornithine transcarbamoylase to increase ammonia detoxification via the urea cycle [122]. Similarly, SIRT5 by deacetylation, desuccinylation, and deglutarylation stimulates the activity of CPS1 [96,102]. Significant amounts of ammonia are created also as a by-product of glutaminolysis. According to previously cited data, SIRT3 enhances the activity of GDH and glutamine influx to the CAC, but SIRT4 and 5 repress this metabolic pathway. Nuclear functions of HIF1α and MYC transcription factors not only affect energetic metabolism, but indirectly also regulate redox status. In short, HIF1α controls glycolysis, while MYC also affects the efficiency of glutaminolysis. An overview of SIRTs metabolic roles suggests antagonistic activity toward HIF1α in the case of SIRT1, 2, 3, 6, and 7, although various mechanisms are related to this interaction. Moreover, MYC functions are affected by SIRT1, 6, and 7, but also SIRT4 via the inhibition of GDH reducing MYC effects on glutaminolysis. Only SIRT2 rather stabilizes MYC transcription factor [36,123]. Irrespective of some exceptions, the active state of sirtuins favors the maintenance of redox balance. In inflammation ROS excessive production is the response to some harmful stimuli, but paradoxically aims to restore previous homeostasis [124]. Proinflammatory signals induce initially acute systemic inflammation. This process starts with the proinflammatory phase, which switches then to the adaptation phase that should finally restore homeostasis [125] (Fig. 10.3A). The proinflammatory phase of inflammation is typically promoted by NF-κB transcription factor activation. In the canonical NF-κB signaling pathway harmful stimuli activate toll-like receptors (TLRs), tumor necrosis factor α (TNFα) induces tumor necrosis factor receptor (TNFR), and interleukin-1 (IL-1) interacts with interleukin-1 receptor (IL-1R). Binding to the receptor leads to an activation of IKKβ (IκB kinase β) in the IKK complex, which can then phosphorylate IKKα (IκB kinase α) on Ser32 and Ser36 residues. Phosphorylation mark is followed by polyubiquitination and proteasomal degradation of IKKα and the release of NF-κB p50 and RelA/p65 subunits, which can translocate into the nucleus and stimulate target genes expression [126,127]. Transformation from the proinflammatory to adaptation phase requires deactivation of NF-κB signaling. De novo synthesis of RelB enables its binding to p50 and replacement of p65/RelA. However, previously p50 p65 heterodimer transcription activity is in addition disrupted by chromatin deacetylation [125 127]. That suggests sirtuins involvement in the switch from acute to adaptation phase. Thus SIRT1 and 6 were shown to interact with NF-κB target genes expression at H3K9 lysine position [27,28,50]. Moreover, SIRT1 directly interacts with and represses the p65/RelA subunit of NF-κB by its deacetylation at Lys310 [14]. The proinflammatory and adaptation phases of inflammation require, as was mentioned earlier, quite different metabolic support. In fact, glycolysis and fatty acids provide the nutritional needs of immune cells [6,128].

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FIGURE 10.3 Overview of metabolic changes in inflammatory cells in relation to cancer. Cellular energy metabolism switches from metabolic balance to the dominance of glycolysis in the proinflammatory phase of inflammation, and further to the dominance of fatty acid β-oxidation in the adaptation phase of inflammation. In addition, the metabolic state is related to NAD1 level and subsequent sirtuins activation/inhibition. (A) Metabolic state of cells and related level of SIRTs activity during classical acute inflammation. (B) Metabolic state of cells and related level of SIRTs activity during chronic inflammation and possible malignant transformation of cell.

Macrophages derived from hematopoietic stem cells are functionally divided into classically activated macrophages (M1 macrophages) and alternatively activated macrophages (M2 macrophages). M1 macrophages are characteristic for the proinflammatory phase in a host defense against bacterial and viral infections, while M2 macrophages are associated, for example, with responses to antiinflammatory reactions [129]. The proinflammatory phase relies on high glycolytic activity, which enables rapid energy production, and additionally activation of the PPP to improve eradication of bacterial infections via the promotion of NADPH oxidase [6,125]. The induction of glucose flux through the glycolytic pathway results from HIF1α transcriptional activity. A high rate of glycolysis decreases AMP/ATP and NAD1/NADH ratios [125]. Sirtuins as the NAD1 level sensors [130] in proinflammatory phase are repressed. The switch to the adaptation phase coexists with energetic reprograming. Cells sense the resulting increase of adenosine monophosphate (AMP) levels, which activates Nicotinamide phosphoribosyltransferase (Nampt) and further Nicotinamide mononucleotide adenylyltransferase (Nmnat) enzymes to produce NAD1, which eventually elevates SIRTs activity [125]. M2 macrophages related to the adaptation phase of inflammation require oxidative metabolism based on fatty acids β-oxidation [128,129]. Three sirtuins were pointed to be crucial in describing the transition of inflammatory phases. Both AMP (particularly AMPK) and NAD1 are the activators of SIRT1—an effective inducer of PGC1 transcription factor that promotes fatty acids β-oxidation and mitochondrial biogenesis [22,131]. There is an advanced antagonistic crosstalk between NF-κB and SIRT1 signaling pathways, with domination of NFκB in the proinflammatory phase and SIRT1 prevalence in the adaptation phase [128]. SIRT6 was described as a master regulator of glucose metabolism, and its high activity suppresses glycolysis mechanistically via contracting the HIF1α metabolic rearrangement [12]. Moreover, SIRT3 is importantly involved in mitochondrial oxidative respiration, being in line with metabolic changes in the second phase of inflammation. Thus after the postinflammation restoration of homeostasis also SIRTs activity tends to be normalized [6,125] (Fig. 10.3A).

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The chronic inflammation together with oxidative stress creates an environment for malignant cells transformation. This facilitates the fact that in chronic inflammation there is a high activity of NF-κB, and also ROS overproduction becomes permanent and no adaptation phase is observed. At low AMP and NAD1 cellular levels sirtuins activity also remains low [6,125]. Finally, a high glycolytic rate can be maintained in an inflammatory environment favoring tumorigenesis (Fig. 10.3B). One of the possibilities to deal with an unstable microenvironment might be promotion of autophagy. In general, autophagy is a process by which damaged proteins and organelles, including mitochondria (mitophagy), are targeted for lysosomal degradation. Such a reutilization process is useful for providing metabolic intermediates during metabolic disabilities [132]. Interplay between sirtuins, cellular energetics, oxidative stress, and inflammation highlights the possible role of SIRTs also in regulation of autophagy. An increase in LC3 (autophagy-related protein 8, Atg8) represents a well-known marker of autophagy taking place in cells. Starvation, as a stress factor, induces translocation of LC3 from the nucleus to the cytoplasm. It was demonstrated that SIRT1 forms complexes with components of autophagy drivers, including LC3, Atg5, and Atg7, to improve its activity via deacetylation [133]. SIRT1 nuclear localization is also related to the preparation of LC3 for translocation to cytoplasm. Only LC3 deacetylated at Lys49 and Lys51 by SIRT1 is proper for interaction with DOR (diabetes- and obesity-regulated nuclear factor), which serves as a carrier for LC3 to translocate it to the cytoplasm and create there autophagosomes [134]. In contrast, SIRT2 was shown to inhibit autophagy, but also improve mitophagy [132]. In glioma cells subjected to hypoxia the lack of SIRT3 expression decreased mitochondrial localization of LC3. Additionally, depletion of mitophagy led to a further decrease in the mitochondrial membrane potential, and increased accumulation of ROS was demonstrated, eventually triggering the degradation of antiapoptotic proteins Mcl-1 and survivin through the proteasomal pathway [135]. Thus the proper activity of SIRT3 and the related induction of mitophagy allow cancer cells to survive. Another example is the role of SIRT5 in forcing LDHB enzymatic activity (deacetylation of Lys329) to convert lactate to pyruvate, with concomitant production of NADPH and H1. Protons generated by LDHB promote lysosomal acidification and autophagy in colorectal cancer cells, finally enhancing tumor growth [108]. SIRT6 is also an autophagy regulator and its expression differs between primary and metastatic melanomas. Particularly, in primary cancer SIRT6 is downregulated, which enables intensive glycolytic metabolism, but it is also correlated with a decrease of autophagy biomarker LC3. However, in advanced, metastatic stages SIRT6 undergoes upregulation to support autophagy as a following mechanism of tumorigenesis maintenance [136].

10.5 Conclusions and perspectives The engagement of sirtuins in the control of cellular energetics and tumor-promoting inflammation represents complex interactions at the level of all cellular compartments. It is impossible to point to an unidirectional role of a particular sirtuin in the tumorigenesis process. Sirtuins, as cellular regulators of homeostasis, normalize bioenergetics metabolism both in inflammatory and cancer cells. Reduced ROS production by inflammatory cells prevents epithelial tissue injury and the creation of microenvironment favoring tumor progression. However, sirtuins are often overexpressed in cancer tissue and act rather as tumor promoters. What decides the net balance between the suppressing and promoting activities of sirtuins requires more comprehensive studies. Similarly a more profound molecular understanding of how specific sirtuins control glycolytic enzymes in resting and activated inflammatory cells, such as macrophages, is likely to deliver new opportunities for manipulating metabolism in these cells as an antiinflammatory strategy for cancer prophylaxis and treatment. Finally, sirtuins can also support cellular functions in stress conditions via the induction of autophagy, although this ability in cancer cells is predominantly negative.

References [1] Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2017;9:7204 18. [2] Hendrayani SF, Al-Harbi B, Al-Ansari MM, Silva G, Aboussekhra A. The inflammatory/cancer-related IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and maintains the active state of breast myofibroblasts. Oncotarget 2016;7:41974 85. [3] Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001;81:807 69.

II. Sirtuins and cancer

References

191

[4] Henrı´quez-Olguı´n C, Altamirano F, Valladares D, Lo´pez JR, Allen PD, Jaimovich E. Altered ROS production, NF-κB activation and interleukin-6 gene expression induced by electrical stimulation in dystrophic mdx skeletal muscle cells. Biochim Biophys Acta 2015;1852:1410 19. [5] Xie J, Zhang X, Zhang L. Negative regulation of inflammation by SIRT1. Pharmacol Res 2013;67:60 7. [6] Vachharajani VT, Liu T, Wang X, Hoth JJ, Yoza BK, McCall CE. Sirtuins link inflammation and metabolism. J Immunol Res 2016;2016:8167273. [7] Semenza GL. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 2007;39:231 4. [8] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646 74. [9] Luo W, Semenza GL. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2011;2:551 6. [10] Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R, et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med 2011;208:313 26. [11] Nakagawa T, Guarente L. Sirtuins at a glance. J Cell Sci 2011;124:833 8. [12] Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010;140:280 93. [13] Liu TF, McCall CE. Deacetylation by SIRT1 reprograms inflammation and cancer. Genes Cancer 2013;4:135 47. [14] Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 2004;23:2369 80. [15] McGettrick AF, O’Neill LA. How metabolism generates signals during innate immunity and inflammation. J Biol Chem 2013;288:22893 8. [16] Zhu L, Zhao Q, Yang T, Ding W, Zhao Y. Cellular metabolism and macrophage functional polarization. Int Rev Immunol 2015;34:82 100. [17] Vazquez A, Liu J, Zhou Y, Oltvai ZN. Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited. BMC Syst Biol 2010;4:58. [18] Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 2010;5:253 95. [19] Chakrabarti P, English T, Karki S, Qiang L, Tao R, Kim J, et al. SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. J Lipid Res 2011;52:1693 701. [20] Simmons Jr GE, Pruitt WM, Pruitt K. Diverse roles of SIRT1 in cancer biology and lipid metabolism. Int J Mol Sci 2015;16:950 65. [21] Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, et al. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev 2010;24:1403 17. [22] Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 2007;26:1913 23. [23] Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxiainducible factor 1alpha. Mol Cell 2010;38:864 78. [24] Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem 2012;287:3850 8. [25] Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 2010;31:89 98. [26] Han L, Zhao G, Wang H, Tong T, Chen J. Calorie restriction upregulated sirtuin 1 by attenuating its ubiquitin degradation in cancer cells. Clin Exp Pharmacol Physiol 2014;41:165 8. [27] Yao H, Rahman I. Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence. Biochem Pharmacol 2012;84:1332 9. [28] Webster BR, Lu Z, Sack MN, Scott I. The role of sirtuins in modulating redox stressors. Free Radic Biol Med 2012;52:281 90. [29] Kleszcz R, Paluszczak J, Baer-Dubowska W. Targeting aberrant cancer metabolism - the role of sirtuins. Pharmacol Rep 2015;67:1068 80. [30] Kumar S, Lombard DB. Mitochondrial sirtuins and their relationships with metabolic disease and cancer. Antioxid Redox Signal 2015;22:1060 77. [31] Liu G, Park SH, Imbesi M, Nathan WJ, Zou X, Zhu Y, et al. Loss of NAD-dependent protein deacetylase sirtuin-2 alters mitochondrial protein acetylation and dysregulates mitophagy. Antioxid Redox Signal 2017;26:849 63. [32] Tsusaka T, Guo T, Yagura T, Inoue T, Yokode M, Inagaki N, et al. Deacetylation of phosphoglycerate mutase in its distinct central region by SIRT2 down-regulates its enzymatic activity. Genes Cells: Devoted Mol Cell Mech 2014;19:766 77. [33] Wong N, De Melo J, Tang D. PKM2, a central point of regulation in cancer metabolism. Int J Cell Biol 2013;2013:242513. [34] Park SH, Ozden O, Liu G, Song HY, Zhu Y, Yan Y, et al. SIRT2-mediated deacetylation and tetramerization of pyruvate kinase directs glycolysis and tumor growth. Cancer Res 2016;76:3802 12. [35] Cha Y, Han MJ, Cha HJ, Zoldan J, Burkart A, Jung JH, et al. Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis. Nat Cell Biol 2017;19:445 56. [36] Ma W, Zhao X, Wang K, Liu J, Huang G. Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer. Cancer Biol Ther 2018;19:835 46. [37] Xu SN, Wang TS, Li X, Wang YP. SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation. Sci Rep 2016;6:32734. [38] Wang F, Tong Q. SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1 repressive interaction with PPARγ. Mol Biol Cell 2009;20:801 8. [39] Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 2005;280:21313 20. [40] Sebastia´n C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 2012;151:1185 99. [41] Lyssiotis CA, Cantley LC. SIRT6 puts cancer metabolism in the driver’s seat. Cell 2012;151:1155 6. [42] Sundaresan NR, Vasudevan P, Zhong L, Kim G, Samant S, Parekh V, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med 2012;18:1643 50.

II. Sirtuins and cancer

192

10. Sirtuins and next generation hallmarks of cancer: cellular energetics and tumor promoting inflammation

[43] Xiao C, Wang RH, Lahusen TJ, Park O, Bertola A, Maruyama T, et al. Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice. J Biol Chem 2012;287:41903 13. [44] Dominy Jr JE, Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol Cell 2012;48:900 13. [45] Zwaans BM, Lombard DB. Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming. Dis Model Mech 2014;7:1023 32. [46] Elhanati S, Kanfi Y, Varvak A, Roichman A, Carmel-Gross I, Barth S, et al. Multiple regulatory layers of SREBP1/2 by SIRT6. Cell Rep 2013;4:905 12. [47] Kanfi Y, Peshti V, Gil R, Naiman S, Nahum L, Levin E, et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 2010;9:162 73. [48] Pike LJ. Lipid rafts: bringing order to chaos. J Lipid Res 2003;44:655 67. [49] Ding X, Zhang W, Li S, Yang H. The role of cholesterol metabolism in cancer. Am J Cancer Res 2019;9:219 27. [50] Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaBdependent gene expression and organismal life span. Cell 2009;136:62 74. [51] Min L, Ji Y, Bakiri L, Qiu Z, Cen J, Chen X, et al. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nat Cell Biol 2012;14:1203 11. [52] Yu W, Yang Z, Huang R, Min Z, Ye M. SIRT6 promotes the Warburg effect of papillary thyroid cancer cell BCPAP through reactive oxygen species. OncoTargets Ther 2019;12:2861 8. [53] Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 2012;487:114 18. [54] Chen S, Seiler J, Santiago-Reichelt M, Felbel K, Grummt I, Voit R. Repression of RNA polymerase I upon stress is caused by inhibition of RNA-dependent deacetylation of PAF53 by SIRT7. Mol Cell 2013;52:303 13. [55] Blank MF, Grummt I. The seven faces of SIRT7. Transcription 2017;8:67 74. [56] Hein N, Hannan KM, George AJ, Sanij E, Hannan RD. The nucleolus: an emerging target for cancer therapy. Trends Mol Med 2013;19:643 54. [57] Hubbi ME, Hu H, Kshitiz, Gilkes DM, Semenza GL. Sirtuin-7 inhibits the activity of hypoxia-inducible factors. J Biol Chem 2013;288:20768 75. [58] Handy DE, Loscalzo J. Redox regulation of mitochondrial function. Antioxid Redox Signal 2012;16:1323 67. [59] O’Malley Y, Fink BD, Ross NC, Prisinzano TE, Sivitz WI. Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem 2006;281:39766 75. [60] Tretter L, Sipos I, Adam-Vizi V. Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson’s disease. Neurochem Res 2004;29:569 77. [61] Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 2014;20:1126 67. [62] Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 2010;35:669 75. [63] Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A 2008;105:14447 52. [64] Cimen H, Han MJ, Yang Y, Tong Q, Koc H, Koc EC. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 2010;49:304 11. [65] Finley LW, Haas W, Desquiret-Dumas V, Wallace DC, Procaccio V, Gygi SP, et al. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS One 2011;6:e23295. [66] Choi JE, Mostoslavsky R. Sirtuins, metabolism, and DNA repair. Curr OpGenet Dev 2014;26:24 32. [67] Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 2010;12:654 61. [68] Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010;464:121 5. [69] Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey DJ, Selen ES, Boersma MD, et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell 2013;49:186 99. [70] Hallows WC, Lee S, Denu JM. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A 2006;103:10230 5. [71] Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A 2006;103:10224 9. [72] Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014;53:534 48. [73] Xu L, Li Y, Zhou L, Dorfman RG, Liu L, Cai R, et al. SIRT3 elicited an anti-Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis. Cancer Med 2019;8:2380 91. [74] Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 2010;40:893 904. [75] Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010;12:662 7. [76] Smolkova´ K, Jeˇzek P. The role of mitochondrial NADPH-dependent isocitrate dehydrogenase in cancer cells. Int J Cell Biol 2012;2012:273947. [77] Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 2011;19:416 28.

II. Sirtuins and cancer

References

193

[78] Finley LW, Haigis MC. Metabolic regulation by SIRT3: implications for tumorigenesis. Trends Mol Med 2012;18:516 23. [79] Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 2009;119:2758 71. [80] Rangarajan P, Karthikeyan A, Lu J, Ling EA, Dheen ST. Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia. Neuroscience 2015;311:398 414. [81] Cui Y, Qin L, Wu J, Qu X, Hou C, Sun W, et al. SIRT3 enhances glycolysis and proliferation in SIRT3-expressing gastric cancer cells. PLoS One 2015;10:e0129834. [82] Haigis MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev 2006;20:2913 21. [83] Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 2013;50:686 98. [84] Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr 2008;28:253 72. [85] Ibdah JA, Paul H, Zhao Y, Binford S, Salleng K, Cline M, et al. Lack of mitochondrial trifunctional protein in mice causes neonatal hypoglycemia and sudden death. J Clin Invest 2001;107:1403 9. [86] Guo L, Zhou SR, Wei XB, Liu Y, Chang XX, Liu Y, et al. Acetylation of mitochondrial trifunctional protein α-subunit enhances its stability to promote fatty acid oxidation and is decreased in nonalcoholic fatty liver disease. Mol Cell Biol 2016;36:2553 67. [87] Betsinger CN, Cristea IM. Mitochondrial function, metabolic regulation, and human disease viewed through the prism of sirtuin 4 (SIRT4) functions. J Proteome Res 2019;18:1929 38. [88] Rowland EA, Snowden CK, Cristea IM. Protein lipoylation: an evolutionarily conserved metabolic regulator of health and disease. Curr OpChem Biol 2018;42:76 85. [89] Mathias RA, Greco TM, Oberstein A, Budayeva HG, Chakrabarti R, Rowland EA, et al. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 2014;159:1615 25. [90] Guarente L. The many faces of sirtuins: sirtuins and the Warburg effect. Nat Med 2014;20:24 5. [91] Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2013;153:840 54. [92] Chen Z, Lin J, Feng S, Chen X, Huang H, Wang C, et al. SIRT4 inhibits the proliferation, migration, and invasion abilities of thyroid cancer cells by inhibiting glutamine metabolism. OncoTargets Ther 2019;12:2397 408. [93] Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013;23:450 63. [94] Colombo SL, Palacios-Callender M, Frakich N, Carcamo S, Kovacs I, Tudzarova S, et al. Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells. Proc Natl Acad Sci U S A 2011;108:21069 74. [95] Huang G, Zhu G. Sirtuin-4 (SIRT4), a therapeutic target with oncogenic and tumor-suppressive activity in cancer. OncoTargets Ther 2018;11:3395 400. [96] Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 2009;137:560 70. [97] Bringman-Rodenbarger LR, Guo AH, Lyssiotis CA, Lombard DB. Emerging roles for SIRT5 in metabolism and cancer. Antioxid Redox Signal 2018;28:677 90. [98] Nishida Y, Rardin MJ, Carrico C, He W, Sahu AK, Gut P, et al. SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol Cell 2015;59:321 32. [99] Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 2013;50:919 30. [100] Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics: MCP 2011;10 M111.012658. [101] Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 2013;18:920 33. [102] Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 2014;19:605 17. [103] Lv XB, Liu L, Cheng C, Yu B, Xiong L, Hu K, et al. SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer. Sci Rep 2015;5:17940. [104] Xiangyun Y, Xiaomin N, Linping G, Yunhua X, Ziming L, Yongfeng Y, et al. Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth. Oncotarget 2017;8:6984 93. [105] Kumar S, Lombard DB. Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology. Crit Rev Biochem Mol Biol 2018;53:311 34. [106] Zhou L, Wang F, Sun R, Chen X, Zhang M, Xu Q, et al. SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep 2016;17:811 22. [107] Xu YS, Liang JJ, Wang Y, Zhao XJ, Xu L, Xu YY, et al. STAT3 undergoes acetylation-dependent mitochondrial translocation to regulate pyruvate metabolism. Sci Rep 2016;6:39517. [108] Shi L, Yan H, An S, Shen M, Jia W, Zhang R, et al. SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. Mol Oncol 2019;13:358 75. [109] Zhang Y, Bharathi SS, Rardin MJ, Lu J, Maringer KV, Sims-Lucas S, et al. Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain. J Biol Chem 2017;292:10239 49. [110] Clark O, Yen K, Mellinghoff IK. Molecular pathways: isocitrate dehydrogenase mutations in cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 2016;22:1837 42. [111] Balendiran GK, Dabur R, Fraser D. The role of glutathione in cancer. Cell Biochem Funct 2004;22:343 52.

II. Sirtuins and cancer

194

10. Sirtuins and next generation hallmarks of cancer: cellular energetics and tumor promoting inflammation

[112] Lin ZF, Xu HB, Wang JY, Lin Q, Ruan Z, Liu FB, et al. SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochem Biophys Res Commun 2013;441:191 5. [113] Lu W, Zuo Y, Feng Y, Zhang M. SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer. Tumour Biol: J Int Soc Oncodev Biol Med 2014;35:10699 705. [114] Zhang Y, Bharathi SS, Rardin MJ, Uppala R, Verdin E, Gibson BW, et al. SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA dehydrogenase. PLoS One 2015;10:e0122297. [115] Polletta L, Vernucci E, Carnevale I, Arcangeli T, Rotili D, Palmerio S, et al. SIRT5 regulation of ammonia-induced autophagy and mitophagy. Autophagy 2015;11:253 70. [116] Zhang M, Wu J, Sun R, Tao X, Wang X, Kang Q, et al. SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS One 2019;14:e0211796. [117] Heinonen T, Ciarlo E, The´roude C, Pelekanou A, Herderschee J, Le Roy D, et al. Sirtuin 5 deficiency does not compromise innate immune responses to bacterial infections. Front Immunol 2018;9:2675. [118] Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860 7. [119] Szade A, Grochot-Przeczek A, Florczyk U, Jozkowicz A, Dulak J. Cellular and molecular mechanisms of inflammation-induced angiogenesis. IUBMB Life 2015;67:145 59. [120] Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science (New York, NY) 2004;303:2011 15. [121] Bauer I, Grozio A, Lasiglie` D, Basile G, Sturla L, Magnone M, et al. The NAD1-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca21 responses. J Biol Chem 2012;287:40924 37. [122] Hallows WC, Yu W, Smith BC, Devries MK, Ellinger JJ, Someya S, et al. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 2011;41:139 49. [123] Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT, Zhang XD, et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ 2013;20:503 14. [124] Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell 2010;140:771 6. [125] Liu TF, Brown CM, El Gazzar M, McPhail L, Millet P, Rao A, et al. Fueling the flame: bioenergy couples metabolism and inflammation. J Leukoc Biol 2012;92:499 507. [126] Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 2013;12:86. [127] DiDonato JA, Mercurio F, Karin M. NF-κB and the link between inflammation and cancer. Immunol Rev 2012;246:379 400. [128] Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 2013;25:1939 48. [129] Chen X, Lu Y, Zhang Z, Wang J, Yang H, Liu G. Intercellular interplay between Sirt1 signalling and cell metabolism in immune cell biology. Immunology 2015;145:455 67. [130] Anderson KA, Madsen AS, Olsen CA, Hirschey MD. Metabolic control by sirtuins and other enzymes that sense NAD1 , NADH, or their ratio. Biochim Biophys Acta Bioenerg 2017;1858:991 8. [131] Mei Z, Zhang X, Yi J, Huang J, He J, Tao Y. Sirtuins in metabolism, DNA repair and cancer. J Exp Clin Cancer Res: CR 2016;35:182. [132] Lee IH. Mechanisms and disease implications of sirtuin-mediated autophagic regulation. Exp Mol Med 2019;51:1 11. [133] Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A 2008;105:3374 9. [134] Huang R, Xu Y, Wan W, Shou X, Qian J, You Z, et al. Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol Cell 2015;57:456 66. [135] Qiao A, Wang K, Yuan Y, Guan Y, Ren X, Li L, et al. Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia. Oncotarget 2016;7:43390 400. [136] Wang L, Guo W, Ma J, Dai W, Liu L, Guo S, et al. Aberrant SIRT6 expression contributes to melanoma growth: role of the autophagy paradox and IGF-AKT signaling. Autophagy 2018;14:518 33.

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C H A P T E R

11 Sirtuins and cellular metabolism in cancers Zhen Dong1,2 and Hongjuan Cui1,2 1

State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture and Textile and Biomass Science, Southwest University, Chongqing, P. R. China 2Cancer Center, Medical Research Institute, Southwest University, Chongqing, P. R. China O U T L I N E 11.1 The metabolic characteristics of cancers 11.1.1 Glucose metabolism in cancers 11.1.2 Lipometabolism in cancers 11.1.3 Other kinds of metabolism in cancers

11.4.2 Direct posttranslational control of OXPHOS by sirtuins 11.4.3 Direct posttranslational control of lipometabolism by sirtuins 11.4.4 Direct posttranslational control of amino acid metabolism by sirtuins

195 196 197 197

11.2 The regulatory modes of sirtuins in controlling cellular metabolism 197 11.3 Direct epigenetic control of cellular metabolism by sirtuins 198 11.3.1 Direct epigenetic control of glucometabolism by sirtuins 198 11.3.2 Direct epigenetic control of lipometabolism by sirtuins 200 11.3.3 Direct epigenetic control of amino acid metabolism by sirtuins 200 11.4 Direct posttranslational control of cellular metabolism by sirtuins 200 11.4.1 Direct posttranslational control of glycolytic enzymes and transporters by sirtuins 200

11.5 Indirect control of cellular metabolism by sirtuins 11.5.1 Indirect control of glycolysis by sirtuins 11.5.2 Indirect control of OXPHOS by sirtuins 11.5.3 Indirect control of lipometabolism by sirtuins 11.5.4 Indirect control of amino acid metabolism by sirtuins

203 204 205 206 208 209 210 211

11.6 Conclusions

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References

211

11.1 The metabolic characteristics of cancers Changes in cellular metabolism are considered as one of the important signs of cancer [1]. Cancer cells change their metabolism, getting the necessary nutrients from an undernourished environment to gain energy and build new biomass [2]. Abnormal cancer metabolism is mainly characterized by upregulation of glucose and amino acid uptake; opportunistic modes of accessing nutrients; increased demand for intermediates in glycolysis/oxidative phosphorylation (OXPHOS), lipometabolism for biosynthesis, and nicotinamide adenine dinucleotide phosphoric acid (NADPH) production; urgent demand for nitrogen; changes in metabolite-driven gene expression and regulation; and metabolic interactions with the tumor microenvironment [3]. From current studies, metabolic reprogramming is considered one of the most important contributors for tumor malignancy and interfering with the metabolism may be a promising strategy for cancer treatment.

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11.1.1 Glucose metabolism in cancers In 1924, German physiologist Otto Heinrich Warburg (19831970) observed that cancer cells prefer to use glycolysis to generate energy in the cytosol, which differs from most normal cells that produce adenosine triphosphate (ATP) by using the OXPHOS/tricarboxylic acid (TCA) cycle in mitochondria (Fig. 11.1) [4]. This phenomenon was later referred to as the “Warburg effect.” This process catalyzes a cytoplasmic pathway that breaks down glucose into two three-carbon compounds, companied by the generation of a small quantity of energy. However, dysfunctional energy metabolism was not recognized as a new hallmark of cancer until 2011 [1]. Recently, more and more evidence indicates that changes in energy metabolism, especially glucose metabolism, such as glycolysis, OXPHOS/TCA cycle, pentose phosphate pathway (PPP), gluconeogenesis, etc., play important roles in tumorigenesis and cancer development [5]. Glucose metabolism is a biochemical process mediated by a series of enzymes and some major regulators that target these enzymes through transcriptional or posttranslational control. Aerobic glycolysis is controlled by a series of enzymes and glucose transporters, including hexokinase II (HK II), aldolase (ALDOA), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase 1 (PGK1), enolase (ENO1), lactate dehydrogenase A (LDHA), pyruvate kinase M2 (PKM2), glucose 6-phosphate dehydrogenase (G6PDH, G6PD), and glucose transporter 1 (GLUT1), which are direct effectors during glycolytic alterations in tumors. These enzymes can also be regulated by some major regulatory factors, such as hypoxia-inducible factors (HIF-1/2), c-Myc and liver kinase B1 (LKB1), and AMP-activated protein kinase (AMPK), or other new regulatory factors can affect aerobic glycolysis through targeting glycolytic enzymes and glucose transporters, thus affecting tumor growth [2]. Actually, the relationship between oncogenes and glucose metabolism shows high crosstalk and has established vicious circles for tumorigenesis [6]. The OXPHOS/TCA cycle is a process in mitochondria in the downstream of glycolysis and a crossroad of the three major metabolic pathways, including glucometabolism, lipometabolism, and protein metabolism. The OXPHOS/TCA cycle—also known as the citric acid cycle (CAC) or the Krebs cycle—is a series of enzymatic chemical reactions that oxidize acetyl-CoA derived from carbohydrates, fats, and proteins, into ATP and carbon dioxide (CO2). The OXPHOS/TCA cycle is controlled by a series of enzymes, such as isocitrate dehydrogenase 2 (IDH2), pyruvate dehydrogenase E1 α1 subunit (PDH-E1, PDHA1), phosphoinositide-dependent kinase-1 (PDK1), and succinate dehydrogenase (SDH). In addition, OXPHOS also has some important regulators, such as the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), manganese-containing superoxide dismutase (MnSOD), dynamin-related protein 1

FIGURE 11.1 Metabolic changes in glucose metabolism in tumors. Normal cells prefer to use OXPHOS in the mitochondria for the production of energy, whereas tumor cells prefer to use aerobic glycolysis for the production of energy and metabolic intermediates.

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197

(Drp1), GA-binding protein transcription factor (GABPα/β), and nuclear respiration factor 1/2 (NRF-1/2), thereby regulating mitochondrial biogenesis, fission/fusion, or function, which is closely related to the energy generated by the OXPHOS/TCA cycle [7]. Although aerobic glycolysis is important, recent studies also reveal that OXPHOS can be also upregulated in certain cancers, even in the face of active glycolysis [8,9]. Increased OXPHOS protects cancer mitochondria from apoptosis-associated permeabilization, reduces aspartate production that leads to impaired nucleotide biosynthesis, or restricts energy support in tumor cells [1012].

11.1.2 Lipometabolism in cancers The reprogramming of lipometabolism, also known as lipid metabolism, has recently been recognized as a new hallmark of cancer progression [1317]. Due to uncontrolled cell growth and rapid metastasis, tumors need to develop efficient production pathways for energy and biomass components. Tumors can strongly activate the endogenous biosynthetic pathway of lipids or increase the uptake of exogenous lipids from the diet. Lipometabolism mainly includes fatty acid (FA) metabolism and cholesterol metabolism. Many reports indicate that fatty acid synthesis (FAS) and oxidation (FAO) are important aspects of lipometabolism reprogramming in tumor cells [18]. In addition, cholesterol metabolism plays an equally important role in tumors as FA metabolism [19]. FA metabolism consists of mitochondrial or peroxisomal FAO and cytoplasmic FAS, both of which are controlled by a series of enzymes. Recently, fat metabolism enzymes such as medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD), very-long-chain acyl-CoA dehydrogenase (VLCAD), carnitine palmitoyl transferase 1a (CPT1 a), and enoyl-CoA hydratase (ECHA) in FAO, as well as ATP citrate lyase (ACLY) and malonyl-CoA decarboxylase (MLYCD) in FAS have been shown to play important roles in tumorigenesis.

11.1.3 Other kinds of metabolism in cancers In addition to glucose metabolism and lipid metabolism, many other metabolic pathways, including amino acid metabolism [20], the urea cycle [21], and nucleotide metabolism [22], are also important for tumor growth, metastasis, and immune response. Among them, glutamine metabolism, also known as glutaminolysis, is the most important metabolic pathway for cancers. Since glutamine is an important carbon source that supplements the TCA cycle, thereby promoting OXPHOS [23], glutamine metabolism has been shown to be related to the cellular biology, physiology, and clinical opportunities of cancers [24,25].

11.2 The regulatory modes of sirtuins in controlling cellular metabolism Recently, increasing evidence has shown that epigenetics plays a pivotal role in cellular metabolism during the tumorigenesis of many kinds of tumors [2630], including glioblastoma [31], melanoma [32], hepatocellular cancer [33], pancreatic cancer [34], and leukemia [35,36]. Even in mitochondria, epigenetics also plays emerging roles during carcinogenesis and tumor progression [37]. There are seven sirtuin members (SIRT1SIRT7) that are expressed in different subcellular locations [7,30]: SIRT1, SIRT6, and SIRT7 are usually located in the nucleus; SIRT2 is usually located in the cytoplasm; SIRT3, SIRT4, and SIRT5 are usually located in the mitochondria. However, sometimes, SIRT1 is also located in the cytoplasm, and SIRT3 is also located in the nucleus [38,39]. This makes sirtuins widely participate in cellular functions, especially cell metabolism regulation from the nucleus, plasma, and mitochondria. The most important regulatory way is epigenetic modulation in the nucleus. Importantly, sirtuin-knockout mice exhibit impressive syndromes related to metabolic alterations [40] (Table 11.1). Unlike other known histone deacetylases that catalyze only acetyllysine residues, sirtuin-mediated deacetylation in acetyllysines depends on nicotinamide adenine dinucleotides 1 (NAD1) hydrolysis [55]. This catalyzing process produces 20 -O-acetyl-ADP-ribose (a substrate for deacetylation) and nicotinamide (NAM), which are feedback inhibitors of the activity of sirtuins [56]. Due to the dependence of sirtuins on NAD1, fluctuations in NAD1 levels will regulate the catalytic activity of sirtuins, which is directly related to the energy state through the ratio of NAD1:NADH in the cell [57]. Sirtuin family proteins share a highly conserved NAD1 binding domain, but have diverse functional domains. Therefore, sirtuins are found to have other catalytic functions [7]. For example, SIRT4 has lower deacetylase activity, but has adenosine diphosphate (ADP)-ribosyltransferase activity;

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TABLE 11.1

Syndrome of sirtuin knockout mice models.

Knockout sirtuin

Syndrome and molecular alterations

References

SIRT1

Majority of mice die prenatally with retinal; cardiac defects; cartilage degradation; increased PPARγ activity, adipogenesis, and insulin sensitivity in adipocytes; enhanced inflammation in kidney and myeloid; hepatic steatosis and inflammation; attenuation in spermatogenesis and germ cell function; repression of forkhead transcription factors

[4146]

SIRT2

Tumor development in mammary (Q) or liver and intestine (R)

[47]

SIRT3

Age-related cardiac hypertrophy; hyperacetylation of mitochondrial proteins without affecting global metabolic homeostasis; change in ACCS2 activity, ATP levels, and mitochondrial protein acetylation

[48,49]

SIRT4

Spontaneously develop several types of tumors; increased mitochondrial GDH activity and upregulation of mitochondrial glutamine metabolism

[50]

SIRT5

No any overt metabolic abnormalities; defect in the urea cycle

[51,52]

SIRT6

Death within 1 month; progeroid syndrome; low levels of serum IGF-1; complete loss of subcutaneous fat; lymphopenia; osteopenia; and acute onset of hypoglycemia, leading to death.

[53]

SIRT7

Reduced life span; ageing-related phenotypes; progressive heart hypertrophy

[54]

SIRT5 also has lysine demalonase, desuccinase, and deglutamylase activities; SIRT6 also has ADP-ribosyltransferase, palmitoylase, and myristoylase activities; SIRT7 also has ADP-ribosyltransferase activity. These enzymes are important erasers of protein modifications both in histones and nonhistone proteins. Therefore sirtuins play essential roles in both epigenetic and posttranslational regulation of cancer metabolism. As important erasers of histones, sirtuins are important epigenetic regulators of key factors regarding cellular metabolism [7,58]. As protein modifying enzymes, sirtuins can regulate metabolic factors in posttranslational levels. Firstly, sirtuins rely on their deacetylase activity to epigenetically regulate the expression of these metabolic genes at the translational level. For instance, SIRT1 deacetylates histone 1 lysine 9 (H3K9) and H4K16 [59]; SIRT2 deacetylates H3K18 and H4K16 [60,61]; SIRT3 deacetylates H4K16, H3K9, and H3K56 [62]; SIRT6 deacetylates H3K9 and H3K56 [63,64]; SIRT7 deacetylates H3K18 [65,66]. SIRT7 also can desuccinylate succinyl-H3K122 in the promoter of the target gene [67]. Besides, they also recruit some transcription factors to initiate transcription. Secondly, sirtuins rely on their catalytic activities such as deacetylation, desuccinylase, demalonylase, demyristoylase, depalmitase, and/or mono-ADP-ribosyltransferase activities to regulate these key enzymes via modulating enzymatic activity, sublocation, and/or stability [7]. Finally, sirtuins regulate major regulators, such as transcription factors, signaling molecules, ubiquitin-ligases, or other factors regarding cellular metabolism by direct or indirect transcription/posttranslational regulation [7].

11.3 Direct epigenetic control of cellular metabolism by sirtuins From current studies (Table 11.2), SIRT1 and SIRT6 are key epigenetic regulators that can modify the status of chromosome remolding by deacetylating the lysines in histone 3 (H3), thereby recruiting transcriptional factors to the promoter of their target metabolic genes, some of which are tightly related to cancer initiation and progression (Fig. 11.2).

11.3.1 Direct epigenetic control of glucometabolism by sirtuins Sirtuins, especially SIRT6, can affect the expression of glycolytic genes encoding enzymes and glucose transporters via an epigenetic route [78]. For example, in the liver, SIRT1 forms a complex with the forkhead box O3 (FOXO3a) and nuclear respiration factor 1 (NRF1, GABPα) on the SIRT6 promoter, and positively regulates the expression of SIRT6, which in turn leads to the H3K9 deacetylation in the promoter of glycolytic genes including glucokinase (GK) and pyruvate kinase liver type (PKL), thereby suppressing their expressions [76]. In tumors, SIRT6 functions as a corepressor of MYC transcription activity by deacetylating histone H3 lysine 9 (H3K9) and histone H3 lysine (H3K56) at the promoter of their target glycolytic genes, including glucose transporter 1 (GLUT1), pyruvate dehydrogenase kinase 1 (PDK1), pyruvate dehydrogenase kinase 4 (PDK4), aldolase/fructose-bisphosphate C (ALDOC), phosphofructokinase1 (PFK1), LDHA, LDHB, triosephosphate isomerase (TPI5), and glyceraldehyde-3-phosphate dehydrogenase

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TABLE 11.2

Epigenetic regulation of cell metabolism by sirtuins.

Sirtuin Transcriptional member Modification factor

Targeted genes

Cell metabolism

Tumors/cells

References

SIRT1

H3K4 Unknown deacetylation

ACC2

Inhibition of the production of malonyl-CoA in triglyceride synthesis

Cervical cancer, pharyngeal squamous, and colorectal cancer

[68]

SIRT6

H3K9 and c-Myc H3K56 deacetylation

GLUT1, PDK4, PDK1, ALDOC, PFK1, LDHB, LDHA, TPI5, and GAPDH

Inhibition of glycolysis

Glioblastoma, melanoma, colorectal cancer, SIRT6 KO H-RasV12/shp53transformed mouse embryonic fibroblasts

[6973]

SIRT6

H3K9 Hif1α deacetylation

GLUT1, PFK1, PDK1, and LDHA

Inhibition of glycolysis

Breast cancer and 293FT

[74,75]

SIRT6

H3K9 Unknown deacetylation

FATP, ACC1, ACC2, Inhibition of FASN, SCD1, ELOVL6, triglyceride synthesis GPAT, DGAT and fat metabolism

Cervical cancer, pharyngeal squamous, and colorectal cancer

[68,76]

SIRT6

H3K56 c-Myc deacetylation

GLS

Inhibition of glutamine uptake

Sirt6 KO H-RasV12/shp53transformed mouse embryonic fibroblasts

[69]

SIRT6

Histone ATF4 lysine deacetylation

SLC6A9, SLC7A1, SLC7A5, SLC36A1, SLC36A4, SLC38A1, and SLC38A3

Inhibition of amino acid uptake

Colon cancer

[77]

FIGURE 11.2 Models of SIRT6-controlled glycolysis in the transcriptional regulation levels. In normal cells, SIRT6 binds to the promoter of a series of glycolytic genes and catalyzes H3K9 and/or H3K56 in the histones, thereby inhibiting the transcriptional activity of transcriptional factors c-Myc or HIF1α and blocking the transcription of these glycolytic genes. In tumor cells, SIRT6 is downregulated and the functions of c-Myc and HIF1α are activated, which further promote the translation of glycolytic genes, thus enhancing the glycolysis and promoting tumorigenesis.

(GAPDH), resulting in the inhibition of aerobic glycolysis and impeding cell proliferation [69,70]. In addition, SIRT6 binds and cosuppresses HIF-1α translational activity and deacetylates H3K9 in the promoter region of several key glycolytic genes, such as GLUT1, PFK1, pyruvate dehydrogenase kinase 1 (PDHK1, also known as PDK1), and LDHA, thus inhibiting its expression [74,79]. In bladder cancers, SIRT1 also promotes the transcriptional activity and expression of GLUT1, resulting in an increase of glucose uptake and tumor progression [80].

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The sirtuins-controlled metabolic processes can also be regulated by many upstream factors. For example, forkhead box O3 (FOXO3a) can also transcriptionally regulate SIRT6, which contributes to tumor growth in both glioblastoma [71], melanoma [72], and colorectal cancers [73] via regulating aerobic glycolysis. In breast cancer, Runt-related transcription factor 2 (RUNX2) negatively regulates SIRT6, inhibiting PDK1 and activating pyruvate dehydrogenase (PDH), which controls the pyruvate metabolism into the TCA cycle [75].

11.3.2 Direct epigenetic control of lipometabolism by sirtuins Sirtuins directly control the transcription of genes encoding lipometabolic enzymes or fatty acid transporters through remodeling chromatin. For example, SIRT1 forms a complex with FOXO3a and NRF1 (GABPα) on the SIRT6 promoter, and positively regulates the expression of SIRT6, and then deacetylates H3K9 in the gene promoter of a series of lipometabolic genes including fatty acid transporter (FATP), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), elongation of very-long-chain fatty acid protein 6 (ELOVL6), CPT1a, 3-phosphoglycerol acyltransferase (GPAT), and diacylglycerol O-acyltransferase (DGAT), thereby negatively regulating triglyceride synthesis and fat metabolism [76]. Another example in cancer cells is the expression of acetyl-CoA carboxylase 2 (ACC2) controlled by SIRT1/6. FAS and FAO are two mutually exclusive pathways that depend on the regulation of malonyl-CoA. This process not only participates in the elongation of fatty acid, but also negatively regulates FAO by inhibiting CPT1a [81]. SIRT1 and SIRT6 can deacetylate H3K9 and histone 4 lysine 8 (H4K8) in the promoter of ACC2, an enzyme that mediates the produce of malonyl-CoA in acidic pH-adapted tumor cells. Therefore the activation of SIRT1/6 results in the promotion of FAO and the reduction of glucose metabolism, while the inhibition of SITR1/6 results in an increase in FAS and a decrease in FAO [68].

11.3.3 Direct epigenetic control of amino acid metabolism by sirtuins Sirtuins also directly control the glutamine metabolism via an epigenetic route. For example, SIRT6 can also deacetylate H3K56 in the promoter region of the glutamine metabolism-related gene glutaminase (GLS) and inhibits its expression by cosuppressing the transcription factor c-Myc and inhibiting c-Myc-regulated glutamine uptake in SIRT6 KO H-RasV12/shp53-transformed mouse embryonic fibroblasts (MEFs) [69]. SIRT6 also functions as a corepressor of the transcriptional activity of activating transcription factor 4 (ATF4), thereby restricting AAT (amino acid transporter) gene expression, including SLC6A9, SLC7A1, SLC7A5, SLC36A1, SLC36A4, SLC38A1, and SLC38A3. However, this axis can be disrupted by NRF2 under glutamine deprivation, leading to the upregulation of amino acid uptake [77]. Recently, SIRT1 was also shown to affect glutamine metabolism. Haploinsufficiency of SIRT1 induces c-Myc expression and several transcriptional targets of c-Myc, including GLUT1, PDK1, SLC1A5, and SLC7A5 that promote glutamine metabolism and sustain colon cancer development [82]. However, whether SIRT1 also epigenetically controls these genes remains unknown.

11.4 Direct posttranslational control of cellular metabolism by sirtuins As important posttranslational enzymes, sirtuins can also directly modify the metabolic enzymes in the posttranslational levels, thereby affecting cancer metabolism and progression (Table 11.3). These modifications usually lead to three different kinds of effects on these enzymes or transporters, that is, enzymatic activity, protein stability, or translocations (Fig. 11.3).

11.4.1 Direct posttranslational control of glycolytic enzymes and transporters by sirtuins Sirtuins affect the enzymatic activity of glycolytic genes through deacetylation or other posttranslational changes. For example, in human fibroblasts, SIRT2 significantly increases OXPHOS and inhibits glycolysis through the deacetylation of glycolytic enzymes such as ALDOA, GAPDH, enolase 1 (ENO1), and PGK1 [83,84]. In HEK293T cells, SIRT2 also deacetylates glucose-6-phosphate dehydrogenase (G6PD) and activates its enzymatic activity, thereby stimulating PPP to provide cytoplasmic NADPH and thus supporting cell survival under oxidative stress [85]. SIRT2 deacetylates PKM2 at K305, thereby reducing PKM2 activity by preventing its tetramerization to develop the active form of enzymatic activity which further inhibits glycolysis and inhibits the

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TABLE 11.3

Direct posttranslational control of ketone body metabolism by sirtuins in cancers.

Sirtuin member Modification

Targeted proteins

SIRT2

Deacetylation

SIRT2

The molecular effect of modifications

Cell metabolism

Tissues/cells

References

ALDOA, Decrease of GAPDH, enzymatic activity ENO1, and PGK1

Promotion of OXPHOS and inhibition of glycolysis

Fibroblasts

[83,84]

Deacetylation

G6PD

Increase of enzymatic activity

Stimulation of PPP pathway

HEK293T cells

[85]

SIRT2

Deacetylation

PKM2

Decrease of enzymatic activity

Inhibition of glycolysis

Tumors

[86]

SIRT2

Deacetylation

PGAM

Increase of enzymatic activity

Increase of glycolysis

Cancer cells and HEK293T cells

[87,88]

SIRT3

Deacetylation

LDHA

Increase of enzymatic activity

Promotion of glycolysis

Gastric cancer

[89]

SIRT5

Deglutarylation

G6PD

Increase of enzymatic activity

Maintenance of cellular NADPH homeostasis and redox potential

murine embryonic fibroblasts (MEFs)

[90]

SIRT5

Desuccinylation

PKM2

Increase of enzymatic activity

Divertion of glucose flux into the pentose phosphate pathway

293T and A549 cells

[91]

SIRT1

Deacetylation

GAPDH

Cytoplasm location Promotion of glycolysis

HeLa and 293FT cells

[92]

SIRT3

Deacetylation

HK2

Mitochondria location

Inhibition of glycolysis

Ovarian cancer

[93]

SIRT3

Deacetylation

CS

Increase of enzymatic activity

Promotion of OXPHOS

Neuroblastoma

[94]

SIRT3

Deacetylation

IDH2

Increase of enzymatic activity

Promotion of OXPHOS and glycolysis

HEK-293T, MCF7 and NIH3T3 cells

[95,96]

SIRT3

Deacetylation

PDHA1, PDP1

Activation of their Promotion of OXPHOS and activity and decrease of glycolysis dissociation of the mitochondrial PDC

H1299 293T, HCT116, HeLa, T47D, MMT, and MCF7 cells

[97,98]

SIRT5

Desuccinylation

PDH-E1, SDH, IDH2

Decrease of enzymatic activity

Maintenance of cellular NADPH homeostasis and redox potential

MEFs and HEK293

[90,99]

SIRT5

Desuccinylation

OGDH

Decrease of enzymatic activity

Reduction of OXPHOS, and induction of mitochondrial membrane potential (ΔΨm), ATP products and increases the ROS levels

Gastric cancer

[100]

SIRT2

Deacetylation

PEPCK

Stabilization of protein

Promotion of gluconeogenesis and supporting TCA cycle and glycolysis

HEK293, 293T, HepG2, and Chang’s liver cells

[101]

SIRT3

Deacetylation

NDUFA9, SDHA, MTATP6

Increase of enzymatic activity

Promotion of ETC function

Drosophila, MEFs, HIB1B and K562 cells

[102104]

SIRT5

Deacetylation

Cyto C

Unknown

Unknown

N.A.

[105] (Continued)

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TABLE 11.3

(Continued)

Sirtuin member Modification

Targeted proteins

SIRT4

ADP-ribosylation

ANT2/3

SIRT3

Deacetylation

SIRT5

The molecular effect of modifications

Cell metabolism

Tissues/cells

References

Increase of enzymatic activity

Inhibition of insulin secretion

Pancreatic β cells

[106]

LCAD

Increase of enzymatic activity

Promotion of FAO

HEK293 cells and mice liver

[107,108]

Desuccinylation

VLCAD

Increase of enzymatic activity

Promotion of FAO

Mice liver

[109]

SIRT3

Deacetylation

VLCAD

Increase of enzymatic activity

Promotion of FAO

Mice liver

[109]

SIRT5

Desuccinylation

ECHA

Increase of enzymatic activity

Promotion of FAO

Mice heart

[110]

SIRT2

Deacetylation

ACLY

Stabilization of protein

Promotion of FAS

HEK293 cells

[111]

SIRT4

Deacetylation

MLYCD

Decrease of enzymatic activity

Promotion of FAS

MEFs and C2C12 cells

[112]

SIRT3

Deacetylation

LCAD

Increase of enzymatic activity

Promotion of FAO

Tibialis anterior [113] and spinal cord of mice

SIRT3

Deacetylation

HMGCS2

Increase of enzymatic activity

Promotion of ketone body formation

HEK293 cells

[114]

SIRT5

Desuccinylation

HMGCS2

Decrease of enzymatic activity

Inhibition of ketone body formation

Mice liver

[115]

SIRT1

Deacetylation

ACSS1

Increase of enzymatic activity

Promotion of FAS

Cos-7 cells

[116]

SIRT3

Deacetylation

ACSS2

Increase of enzymatic activity

Promotion of fatty acid synthesis

HEK293, COS1, and HeLa cells

[117]

SIRT4

ADP-ribosylation

GDH1

Inhibition of enzymatic activity

Inhibition of glutamine metabolism Hepatoma cells

[118]

SIRT4

Delipoylation

DLAT

Diminishment of PDH activity

Glutamine

MEFs

[119]

SIRT3

Deacetylation

GDH1

Increase of enzymatic activity

Support of glutamine metabolism

Renal cell carcinoma

[82]

SIRT3

Deacetylation

GOT2

Enhancement of Regulation of malate-aspartate the protein NADH shuttle interaction between GOT2 and MDH2

Pancreatic tumor

[120]

SIRT5

Desuccinylation

GLS

Inhibition of enzymatic activity

MDA-MB-231 [121] and C2C12 cells

SIRT4

Demethylglutarylation, dehydroxymethylglutarylation and de-3-methylglutarylation

MCCC

Increase of stability Promotion of leucine oxidation

Liver, heart, and/or skeletal muscle of mice

[122]

SIRT5

Deacetylation, desuccinylation, CPS1 and deglutamylation

Increase of enzymatic activity

Mice liver and 293T

[52]

Conversion of glutamine to glutamic acid in the production of ammonia

Promotion of urea cycle

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FIGURE 11.3 Models of sirtuins’ demodifications and their effects on proteins (some examples). Typically, release of these covalent modifications (most of them are deacetylation) leads to three different alterations in protein: alterations of enzymatic activity, affects on protein stability, and translocations.

growth of malignant tumors [86]. SIRT2 can also deacetylate phosphoglycerate mutase (PGAM) on lysine 100/106/113/138 to regulate its enzymatic activity, which coordinates the energy produced by glycolysis and decreases reducing power and the biosynthesis of uridine precursors and amino acids, thereby playing an important role in regulating cell proliferation and tumor growth [87,88]. However, the exact promotion or inhibition of PGAM by SIRT2 deacetylation should be further clarified. SIRT3 also directly participates in the glycolytic process by regulating the activity of glycolytic enzymes. SIRT3 interacts with LDHA and enhances its activity by deacetylation to promote the expression of glycolysis-related genes in gastric cancer cells overexpressing SIRT3 [89] and may also contribute to tumor progression of cervical cancer [123] and ovarian cancer [124]. SIRT4 also shows a potential to regulate glycolysis; however, the detailed molecular mechanism remains unknown [125]. SIRT5 is also located in mitochondria and regulates mitochondrial function. Unlike other sirtuins, SIRT5 shows a unique affinity for deacetylation and catalyzes desuccinylation, demalonylation and deglutarization of proteins [126]. For example, SIRT5 promotes G6PD deglutarylation to regulate cell NADPH homeostasis and redox potential [90]. SIRT5 desuccinylates PKM2 on K49, which contributes to the antioxidant response and inhibits tumor cell proliferation [91]. SIRT5 also can be suppressed by CDK2, resulting in the downregulating of aerobic glycolysis in gastric cancer [127]. In addition, sirtuins also affect the sublocations of these enzymes, thereby controlling glucose metabolism. For example, SIRT1 interacts with GAPDH and retains it in the cytoplasm, thereby protecting the enzyme from nuclear translocations, promoting glycolysis, and inducing apoptosis through radiation and other means to regulate cell survival [92]. SIRT3 also increases the level of HK2 localization at the mitochondria, thereby inhibiting the glycolysis of ovarian cancer cells [93].

11.4.2 Direct posttranslational control of OXPHOS by sirtuins As a mitochondrial factor, SIRT3 is not only involved in the regulation of glycolysis, but also in the regulation of mitochondrial function. Its biological process is directly related to the OXPHOS/TCA cycle. SIRT3 directly

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regulates the OXPHOS/TCA cycle by regulating enzyme activity in the TCA cycle. For instance, SIRT3 deacetylates acetyl groups of citrate synthase (CS) and activates its activity in neuroblastoma SH-SY5Y cells [94]. In addition, SIRT3 deacetylates IDH2 and promotes OXPHOS, thereby increasing NADPH levels and the abundance of active glutathione [95]. SIRT3 deacetylates IDH2 at K413, thereby increasing its enzymatic activity by reducing the formation of IDH2 dimers, which further increases the cell’s reactive oxygen species (ROS) and glycolysis [96]. In addition, in epidermal growth factor (EGF) stimulated cells and cancer cells, SIRT3 deacetylates PDHA1 at K321 and pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) at K202, thereby activating their activity and dissociating the mitochondrial pyruvate dehydrogenase complex (PDC), which further promotes OXPHOS and reduces glycolysis in cancer cells, leading to subsequent tumor growth [97,98]. Another mitochondrial sirtuin, SIRT5, also regulates enzymes in the OXPHOS/TCA cycle. For example, SIRT5 controls glucose oxidation by directly desuccinating these enzymes to inhibit PDH-E1 and SDH activity [99]. SIRT5 also promotes desuccinylation of IDH2, which regulates the homeostasis and redox potential of cell NADPH [90]. Recently, SIRT5 was also shown to desuccinate oxoglutarate dehydrogenase (OGDH) and inhibit its enzymatic activity, thereby inhibiting cell proliferation and migration in gastric cancer [100]. In addition to mitochondrial sirtuins, other members of the sirtuin family are also directly involved in the regulation of the OXPHOS/TCA cycle. For example, SIRT2 deacetylates and stabilizes phosphoenolpyruvate carboxykinase (PEPCK), thereby catalyzing the rate-limiting, irreversible step of gluconeogenesis, thereby generating pyruvate to provide energy for the TCA cycle and glycolysis [101]. Importantly, sirtuins also affect the function of the electronic transmission chain (ETC), thereby regulating the OXPHOS/TCA cycle. SIRT3 deacetylates several components of the ETC including complex I (such as NADH dehydrogenase (ubiquinone) 1α subcomplex 9, NDUFA9), several complexes II (succinate dehydrogenase complex flavin protein subunit A, SDHA), and complex V (ATP synthase subunit β, MTATP6) [102104]. Importantly, SIRT3 has been shown to aggravate mitochondrial complex I inhibitors, metformin-induced energy stress, and induce cell apoptosis in ovarian cancer. In addition, other sirtuins also play an important role in ETC. SIRT5 can be transferred to the mitochondrial intermembrane space (MIS) and deacetylated cytochrome c (Cyto C), a protein of MIS that has important functions in ETC and can initiate apoptosis [105]. It has been shown that SIRT4 binds to the ADP/ATP carrier protein adenine nucleotide transporter 2/3 (ANT2/3), which transports ATP into the cytoplasm and ADP into the mitochondrial matrix, thereby providing a base for ATP synthase [106]. In addition, it appears that SIRT1 can promote mRNA levels of NDUFA10, one of the subunits of complex I [128]. However, the regulatory mode of SIRT1 and SIRT4 in the regulation of ETC should be further confirmed.

11.4.3 Direct posttranslational control of lipometabolism by sirtuins Generally, sirtuins bind to lipometabolism-related enzymes and modify them under translational levels to activate their activity. For example, in FAO, SIRT3 stimulates FAO through the deacetylation and activation of longchain specific acyl-CoA dehydrogenase (LCAD) [107,108], a key enzyme that catalyzes a long-chain acyl-CoA to a long-chain trans-2,3-dehydroacyl-CoA. SIRT5 desuccinylation and SIRT3 deacetylation stimulate VLCAD, a key enzyme that can catalyze a very-long-chain acyl-CoA to a long-chain trans-2,3-dehydroacyl-CoA, thereby promoting FAO [109]. SIRT5 can also desuccinylate and activate ECHA, an enzyme that catalyzes the formation of hydroxyacyl-CoA from enoyl-CoA, thereby inducing FAO [110]. There is also a similar effect of SIRT5 in the peroxisome lipid metabolism pathway [129]. Deletion of SIRT5 results in the accumulation of medium- and longchain acylcarnitines and inhibits FAO [115]. At the same time, sirtuins also play important roles in deacetylating enzymes involved in FAS. For example, SIRT2 deacetylates and destabilizes ACLY, which regulates the production of acetyl-CoA and causes FAS inhibition [111]. SIRT4 deacetylates the enzyme MLYCD, which catalyzes the formation of malonyl-CoA, and inhibits its activity. Malonyl-CoA provides a carbon backbone for lipid anabolic metabolism and reduces FAO [112]. Acetate is transported into cells by members of the monocarboxylate transporter family, and is catalyzed into acetyl by acyl-CoA synthetase short-chain family member 1 (ACSS1) and acyl-CoA synthetase short-chain family member 2 (ACSS2). As a substrate for fatty acid synthesis, acetyl-CoA is present in most cancer cells to establish sufficient lipid biomass as a fuel to support cell proliferation [130,131]. Recently, sirtuins including SIRT1 and SIRT3 have been shown to play an important role in directly regulating the enzyme activity of ACSS1 and ACSS2, respectively. SIRT1 deacetylates and activates ACSS1, thereby enhancing FAS [116]. SIRT3 deacetylates and stimulates ACSS2, causing a 10-fold increase in carbon dioxide [117].

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Ketone bodies, including β-hydroxybutyrate (PHB), acetoacetate, and acetone, are usually produced in the liver during starvation and function as mitochondrial fuels [132]. Recently, ketone bodies function as cancer metabolites that drive tumor growth and metastasis, such as hydroxymethylglutaryl coenzyme A synthase 2 (HMGCS2), acetyl coenzyme A acetyltransferase 1/2 (ACAT1/2), and 3-oxo acid coenzyme A transferase 1/2 (OXCT1/2) [133]. Importantly, sirtuins have also been shown to have direct regulatory capabilities in regulating the activity of these enzymes. SIRT3 promotes ketone body production in FAO by activating HMGCS2, the rate-limiting enzyme for ketone body formation, and indirectly regulates FAO [113,114]. SIRT5 introduces the desuccinylation of HMGCS2, reduces HMGCS2 activity, and leads to reduced PHB production in the body, which means that SIRT5 is involved in ketone body metabolism [115].

11.4.4 Direct posttranslational control of amino acid metabolism by sirtuins SIRT4 catalytic efficiency for lipoyl-, biotinyl-lysine, and ADP-ribosyl modifications is superior to its deacetylation activity. Recent reports indicate that mitochondrial SIRT4 plays an important role in regulating glutamine metabolism through ADP-ribosylated glutamate dehydrogenase 1 (GLUD1, also known as GDH1 or GLDH1) [118]. Alternatively, SIRT4 hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity, leading to a metabolic flux switching via glutamine stimulation [119]. SIRT4 inhibits tumorigenesis by inhibiting mitochondrial glutamine metabolism, which responds to DNA damage and inhibits tumor activity, including c-Myc-driven human Burkitt lymphoma and colorectal cancer cells [50,134136]. Importantly, the reduced glutamine utilization induced by SIRT4 makes tumors sensitive to glucose consumption [135]. In thyroid cancer cells, SIRT4-suppressed glutamine metabolism also impedes the proliferation, migration, and invasion abilities [137]. In addition, glutamine metabolism regulated by SIRT4 is also affected by other regulators. For example, C-terminal binding protein 1 (CtBP) inhibits SIRT4 expression, thereby promoting glutamine breakdown in cancer cells [138]. The CtBP-SIRT4 axis also coordinates the glycolysis and glutamine metabolism in cancer cells. CtBP represses SIRT4 expression only under a high level of glucose but not low, because in the latter condition, CtBP binding to SIRT4 promoter is abolished [139]. The mechanistic target of rapamycin kinase complex 1 (mTORC1) promotes proteasome-mediated instability of cAMP response element binding protein 2 (CREB2), a factor that promotes SIRT4 transcription [136]. SIRT4 can also be transcriptionally inhibited by HUTF1, thereby mediating UHRF1-promoted cell metabolism switching in pancreatic cancers possibly through SIRT4-suppressed PDH activity [123]. In addition to SIRT4, other sirtuins also have the ability to regulate glutamine metabolism through a variety of regulation methods. For example, SIRT3 enhances GLUD1 ability to regulate glutamine-dependent oxidation, increases mitochondrial oxygen consumption, and supports tumor growth in renal cell carcinoma [82]. In diffuse large B cell lymphomas (DLBCLs), SIRT3 depletion impairs glutamine flux to the TCA cycle, leading to a reduction in acetylCoA pools that in turn induce autophagy and cell death [140]. In clear cell renal carcinoma, SIRT3-regulated glutaminosis also promotes cell proliferation [141]. In addition, SIRT3 deacetylates mitochondrial glutamate oxaloacetate aminotransferase (GOT2), a key enzyme that controls the malateaspartate NADH shuttle and is located at K159, K185, and K404. This shuttle is important for transferring NADH from the cytosol to the mitochondria to maintain a high ratio of glycolysis in tumor cells. Increased GOT2 acetylation in the absence of SIRT3 promotes a net transfer of cytosolic NADH to the mitochondria, thereby supporting the production of ATP and the proliferation of cancer cells. Importantly, increased acetylation of GOT2 K159 in human pancreatic tumors is associated with decreased SIRT3 expression [120]. At the same time, SIRT5 has also been reported to desuccinylate and inhibit GLS, which catalyzes the conversion of glutamine to glutamic acid in the production of ammonia and ammonia-induced autophagy in nonammonia cells [121]. Importantly, SIRT5 has also been reported to regulate ammonia production and ammonia-induced autophagy in nonhepatocytes by regulating glutamine metabolism. Mechanistically, SIRT5 can desuccinylate at K158 and K164 sites of GLS and inhibit GLS, an enzyme that catalyzes the conversion of glutamine to glutamic acid in a reaction that produces ammonia, thereby promoting autophagy [121,139]. In transformed cells and human breast tumors, the SIRT5-GLS axis also plays an important role in glutamine metabolism [142]. This evidence suggests that sirtuins regulate cellular metabolism in a highly intertwined manner. SIRT5 is also responsible for the urea cycle. SIRT5 regulates the urea cycle by deacetylating, desuccinylating, and deglutamylating carbamoyl phosphate synthase 1 (CPS1), thereby increasing its activity [143,144]. CPS1 catalyzes the first step of the urea cycle for ammonia detoxification in the liver and, to a lesser extent, in the kidney [52].

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Aside from glutamine metabolism, SIRT4 is also responsible for leucine metabolism. In SIRT4 KO mice, leucine metabolism disorders lead to increased basal metabolism and insulin secretion, which gradually develop into glucose intolerance and insulin resistance [122]. In addition, SIRT4 removes three acyl moieties from lysine residues, including methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaryl (MGc)-groups, thus providing an intermediate for leucine oxidation [122].

11.5 Indirect control of cellular metabolism by sirtuins Cellular metabolism is also controlled by some major regulators, including metabolism-specific transcriptional factors, signaling transduction pathways, as well as some growth factors, oncogenes, and tumor suppressors. Recently, sirtuins also regulate these factors in both transcriptional, posttranslational, or upstream factors that modulate these major regulators (Table 11.4). For instance, the PGC1α is key regulator of glucogenesis which can be regulated by SIRT1 and SIRT6 (Fig. 11.4). TABLE 11.4

Modulation of major regulators of cellular metabolism by sirtuins.

Targeted Sirtuin proteins/ member Modification genes

The molecular effect of modifications

Cell metabolism

Tumors/cells

References

SIRT1

Deacetylation HIF1/2

Inhibition of translational activity

Inhibition of glycolysis

Hep3B, HT1080, and HEK293 cells

[145,146]

SIRT2

Deacetylation HIF-1

Increase of stability

Promotion of glycolysis

HeLa cells

[147]

SIRT3

Deacetylation HIF-1α

Decrease of stability

Decrease of glycolysis

Breast cancer, colorectal cancer, and cholangiocarcinoma

[148152]

SIRT7

Deacetylation HIF-1/2

Decrease of stability

Decrease of glycolysis (possible)

Hep3B and HeLa cells

[153]

SIRT1

Deacetylation c-Myc

Promotion of c-Myc/Max association

Promotion of glycolysis

HeLa, HO15, K562, HEK293, 293A cells, and Burkitt lymphoma cells

[154157]

SIRT2

H4K16 NEDD4 Deacetylation

Repression of NEDD4 gene Promotion of glycolysis expression and protection of N- (possible) Myc and c-Myc from ubiquitination degradation

Neuroblastoma and pancreatic cancer

[158]

SIRT7

H3K18 c-Myc Deacetylation

Inhibition of Myc transcriptional activity

Inhibition of lipogenesis.

Mice liver

[159]

SIRT1

Deacetylation LKB

Activation of LKB activity

Inhibition of FAS

HEK293T, HepG2 cells, and osteosarcoma

[160162]

SIRT3

Deacetylation PTEN

Decrease of stability

Inhibition of glycolysis

p53 wild-type cancer

[163]

SIRT2

Deacetylation APC(CDH1) and CDC20

Decrease of the anaphasepromoting complex/cyclosome activity

Inhibition of the SH-SY5Y and HEK293 cells Warburg effect (possible)

[47,164]

SIRT3

Deacetylation Cyclophilin D

Diminishment of the peptidylprolyl cis-trans isomerase activity

Inhibition of glycolysis

Breast cancer

[165]

SIRT1/6 Deacetylation hnRNPA1

Reduction of the alternative splicing capacity of the pyruvate kinase (PK) mRNA

Inhibition of glycolysis

Hepatocellular carcinoma
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