Sirtuin (silent information regulator 2-related proteins, SIRT) enzymes belong to a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases present in organisms ranging from bacteria to mammals and catalyze the removal acetyl of lysine residues in proteins to regulate acetyl-based physiological processes. The family is characterized by homology with the yeast protein silent information regulator 2 (Sir2) [1]. First, Sir2 was described as a regulator of transcriptional silencing of mating-type loci, telomeres, and ribosomal DNA, promoting the replicative lifespan in yeast; deletion of Sir2 shortens yeast lifespan, and Sir2 overexpression extends yeast lifespan [2], [3]. Then, as Sir2 was found to be an NAD+-dependent histone deacetylase (HDAC), it has been revealed that SIRTs function as both energy sensors and transcriptional effectors by controlling the acetylation state of histones [4]. Further studies have demonstrated that SIRTs deacetylate histones and a wide range of transcriptional regulators [5].

Seven SIRT homologs (SIRT1-7) sharing a common catalytic core have been identified in mammals. The variety of subcellular locations of each isoform has been proposed to modulate specific biological functions. SIRT1 functions in the nucleus but also the cytoplasm [6]. SIRT6 and SIRT7 are nucleoproteins, while SIRT3-5 are localized in the mitochondria [7]. SIRT2, also known as SIR2, SIRT type 2, or Sir2‐related protein type 2, is the only isoform that predominantly resides in the cytoplasm and is also found in the mitochondria and the nucleus [8]. SIRTs can remove succinyl, malonyl, glutaryl, crotonyl, decanoyl, myristoyl, palmitoyl, and other long-chain fatty acyl groups reversibly from histones (H1, H2, H3) and non-histone (p53, p65, p300, PGC-1α, PPARγ, FOXO, NFκB, Ku70, HIF1α, and α-tubulin) proteins, but also display unique acyl-lysine substrate preferences [9], [10], [11], [12]. SIRTs catalyze the deacetylation reaction using NAD+ as a co-substrate to produce the deacetylated protein substrate, O-acetyl-ADP-ribose, and nicotinamide, the endogenous SIRT inhibitor [13]. SIRTs conduct several physiological pathways related to genome stability, tumorigenesis, stress response, metabolism, and inflammation. Regarding their important roles at the cellular level, they have been associated with cancer, inflammation, cardiovascular, and neurodegenerative diseases [14].

Among all, interest in SIRT2 has increased continuously over recent years, resulting in accumulated evidence leading to uncovering many substrates and additional functions of SIRT2 [15]. The studies suggest that SIRT2 significantly regulates multiple biological processes, including energy metabolism, cell cycle regulation, autophagy, DNA repair, genome integrity, and oxidative stress [16], [17], [18], [19]. The aberrant activity of SIRT2 has been linked to various pathophysiological conditions such as cancer, neurodegenerative disorders, and metabolic syndrome. Therefore, targeting the activity of SIRT2 using developed small molecules holds therapeutic promise in treating a wide variety of diseases. Regarding tumorigenesis, the prominent role of SIRT2 has been debated since it functions either as a tumor suppressor or as an oncogene, depending on the experimental conditions. Accordingly, this article will review the emerging understanding of the molecular basis of action of SIRT2 in different types of cancer and highlight the advantage of SIRT2 selective inhibitors as potential anticancer therapeutics.