Emerging Roles for SIRT5 in Metabolism and Cancer

Overview

Journal Antioxid Redox Signal

Specialty Endocrinology

Date 2017 Jul 15

PMID 28707979

Citations 63

Authors

Lauren R Bringman-Rodenbarger

Angela H Guo

Costas A Lyssiotis

David B Lombard

Affiliations

Soon will be listed here.

Abstract

Significance: Developing evidence in the literature suggests that sirtuin 5 (SIRT5) may be involved in metabolic reprogramming, an emerging hallmark of cancer by which neoplastic cells reconfigure their metabolism to support the anabolic demands of rapid cell division. SIRT5 is one of the seven members of the nicotinamide adenine dinucleotide-dependent sirtuin family of lysine deacetylases. It removes succinyl, malonyl, and glutaryl groups from protein targets within the mitochondrial matrix and other subcellular compartments. SIRT5 substrates include a number of proteins integral to metabolism. Recent Advances: New work has begun to elucidate the roles of SIRT5 in glycolysis, tricarboxylic acid cycle, fatty acid oxidation, nitrogen metabolism, pentose phosphate pathway, antioxidant defense, and apoptosis.

Critical Issues: In this study, we summarize biological functions of SIRT5 reported in normal tissues and in cancer and discuss potential mechanisms whereby SIRT5 may impact tumorigenesis, particularly focusing on its reported roles in metabolic reprogramming. Finally, we review current efforts to target SIRT5 pharmacologically.

Future Directions: The biological significance of SIRT5 has been elucidated in the context of only an extremely small fraction of its targets and interactors. There is no doubt that further studies in this area will provide a wealth of insights into functions of SIRT5 and its targets in normal and neoplastic cells. Antioxid. Redox Signal. 28, 677-690.

Citing Articles

SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1.

Zhao Q, Jing Y, Jiang X, Zhang X, Liu F, Huang H Nat Metab. 2025; .

PMID: 40087407 DOI: 10.1038/s42255-025-01235-8.

SIRT7 affects the proliferation and apoptosis of papillary thyroid cancer cells by desuccinylation of LATS1.

Li Q, Pu G BMC Cancer. 2025; 25(1):408.

PMID: 40050771 PMC: 11887367. DOI: 10.1186/s12885-025-13779-9.

SIRT5: a potential target for discovering bioactive natural products.

Xie Y, Cai N, Liu X, He L, Ma Y, Yan C J Nat Med. 2025; .

PMID: 39979670 DOI: 10.1007/s11418-024-01871-6.

Sirtuins as Key Regulators in Pancreatic Cancer: Insights into Signaling Mechanisms and Therapeutic Implications.

Chouhan S, Kumar A, Muhammad N, Usmani D, Khan T Cancers (Basel). 2024; 16(23).

PMID: 39682281 PMC: 11640239. DOI: 10.3390/cancers16234095.

SIRT5 inhibits glycolysis and nasal type extranodal NK/T cell lymphoma cell proliferation by catalyzing the desuccinylation of glucose-6-phosphate isomerase.

Wang T, Tan G, Jiang M, Liu G, Li W, Qing X Transl Oncol. 2024; 51:102215.

PMID: 39615276 PMC: 11647232. DOI: 10.1016/j.tranon.2024.102215.

References

Boylston J, Sun J, Chen Y, Gucek M, Sack M, Murphy E . Characterization of the cardiac succinylome and its role in ischemia-reperfusion injury. J Mol Cell Cardiol. 2015; 88:73-81. PMC: 4780049. DOI: 10.1016/j.yjmcc.2015.09.005. View

Sun J, Xu L, Tseng H, Ciccarelli B, Fulciniti M, Hunter Z . Histone deacetylase inhibitors demonstrate significant preclinical activity as single agents, and in combination with bortezomib in Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011; 11(1):152-6. DOI: 10.3816/CLML.2011.n.036. View

Miao P, Sheng S, Sun X, Liu J, Huang G . Lactate dehydrogenase A in cancer: a promising target for diagnosis and therapy. IUBMB Life. 2013; 65(11):904-10. DOI: 10.1002/iub.1216. View

Taylor W, Mejia E, Mitchell R, Choy P, Sparagna G, Hatch G . Human trifunctional protein alpha links cardiolipin remodeling to beta-oxidation. PLoS One. 2012; 7(11):e48628. PMC: 3494688. DOI: 10.1371/journal.pone.0048628. View

Du J, Zhou Y, Su X, Yu J, Khan S, Jiang H . Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science. 2011; 334(6057):806-9. PMC: 3217313. DOI: 10.1126/science.1207861. View

Wang F, Nguyen M, Qin F, Tong Q . SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell. 2007; 6(4):505-14. DOI: 10.1111/j.1474-9726.2007.00304.x. View

Wagner G, Hirschey M . A Prob(e)able Route to Lysine Acylation. Cell Chem Biol. 2017; 24(2):126-128. PMC: 5503691. DOI: 10.1016/j.chembiol.2017.01.011. View

Vahtola E, Louhelainen M, Merasto S, Martonen E, Penttinen S, Aahos I . Forkhead class O transcription factor 3a activation and Sirtuin1 overexpression in the hypertrophied myocardium of the diabetic Goto-Kakizaki rat. J Hypertens. 2008; 26(2):334-44. DOI: 10.1097/HJH.0b013e3282f293c8. View

Lai C, Lin P, Lin S, Hsu C, Lin H, Hu M . Altered expression of SIRT gene family in head and neck squamous cell carcinoma. Tumour Biol. 2013; 34(3):1847-54. DOI: 10.1007/s13277-013-0726-y. View

10.

Wang F, Wang K, Xu W, Zhao S, Ye D, Wang Y . SIRT5 Desuccinylates and Activates Pyruvate Kinase M2 to Block Macrophage IL-1β Production and to Prevent DSS-Induced Colitis in Mice. Cell Rep. 2017; 19(11):2331-2344. DOI: 10.1016/j.celrep.2017.05.065. View

11.

Li F, He X, Ye D, Lin Y, Yu H, Yao C . NADP(+)-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance. Mol Cell. 2015; 60(4):661-75. DOI: 10.1016/j.molcel.2015.10.017. View

12.

Yang L, Ma X, He Y, Yuan C, Chen Q, Li G . Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors. Sci China Life Sci. 2016; 60(3):249-256. DOI: 10.1007/s11427-016-0060-7. View

13.

Hebert A, Dittenhafer-Reed K, Yu W, Bailey D, Selen E, Boersma M . Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell. 2012; 49(1):186-99. PMC: 3704155. DOI: 10.1016/j.molcel.2012.10.024. View

14.

Yu H, Pardoll D, Jove R . STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009; 9(11):798-809. PMC: 4856025. DOI: 10.1038/nrc2734. View

15.

Bowman C, Rodriguez S, Alpergin E, Acoba M, Zhao L, Hartung T . The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency. Cell Chem Biol. 2017; 24(6):673-684.e4. PMC: 5482780. DOI: 10.1016/j.chembiol.2017.04.009. View

16.

Houtkooper R, Pirinen E, Auwerx J . Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012; 13(4):225-238. PMC: 4872805. DOI: 10.1038/nrm3293. View

17.

Marcon E, Jain H, Bhattacharya A, Guo H, Phanse S, Pu S . Assessment of a method to characterize antibody selectivity and specificity for use in immunoprecipitation. Nat Methods. 2015; 12(8):725-31. DOI: 10.1038/nmeth.3472. View

18.

Rhodes D, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs B . Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007; 9(2):166-80. PMC: 1813932. DOI: 10.1593/neo.07112. View

19.

Lombard D, Zwaans B . SIRT3: as simple as it seems?. Gerontology. 2013; 60(1):56-64. PMC: 3875292. DOI: 10.1159/000354382. View

20.

Lin Z, Xu H, Wang J, Lin Q, Ruan Z, Liu F . SIRT5 desuccinylates and activates SOD1 to eliminate ROS. Biochem Biophys Res Commun. 2013; 441(1):191-5. DOI: 10.1016/j.bbrc.2013.10.033. View