Emerging Roles for SIRT5 in Metabolism and Cancer

Abstract

Significance: Developing evidence in the literature suggests that 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. Sirtuin 5 (SIRT5) is one of the seven members of the nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin family of lysine deacylases. It removes succinyl, malonyl, and glutaryl groups from protein targets within the mitochondrial matrix and other subcellular compartments. SIRT5’s substrates include a number of proteins integral to metabolism. Recent Advances: New work has begun to elucidate the roles of SIRT5 in glycolysis, TCA cycle, FAO, nitrogen metabolism, pentose phosphate pathway, antioxidant defense, and apoptosis. Critical Issues: Here, 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. No doubt further studies in this area will provide a wealth of insights into functions of SIRT5 and its targets in normal and neoplastic cells.