The emerging and diverse roles of sirtuins in cancer: a clinical perspective

Abstract

Sirtuins are a highly conserved family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein lysine modifying enzymes with deacetylase, adenosine diphosphateribosyltransferase and other deacylase activities. Mammals have seven sirtuins, namely SIRT1-7. They are key regulators for a wide variety of cellular and physiological processes such as cell proliferation, differentiation, DNA damage and stress response, genome stability, cell survival, metabolism, energy homeostasis, organ development, aging, and cancer. Here we present an extensive literature review of the roles of mammalian sirtuins, particularly SIRT1 as that is the most studied sirtuin, in human epithelial, neuronal, hematopoietic, and mesenchymal malignancies, covering breast, prostate, lung, thyroid, liver, colon, gastric, pancreatic, ovarian, and cervical cancers, tumors of the central nervous system, leukemia and lymphoma, and soft tissue sarcomas. Collective evidence suggests sirtuins are involved in both promoting and suppressing tumorigenesis depending on cellular and molecular contexts. We discuss the potential use of sirtuin modulators, especially sirtuin inhibitors, in cancer treatment.

Keywords: acetylation; cancer; deacetylation; sirtuin; sirtuin modulator.

Figure 1

Bifurcated roles of SIRT1 in tumor promotion and suppression. Abbreviations: APE1, apurinic/apyrimidinic endonuclease-1; FOXO, forkhead box protein O; HIF-1 α, hypoxia-inducible factor 1-al pha; MMP2, matrix metalloproteinase-2; NBS1, nijmegen breakage syndrome protein 1; NIC, Notch 1 intracellular domain; PARP 1, poly(adenosine diphosphate ribose) polymerase 1; WRN, Werner syndrome; Xpa, xeroderma pigmentosum group A; Xpc, xeroderma pigmentosum group C; ZEB1, zinc finger E-box-binding homeobox 1.

Figure 2

Various scaffolds of known sirtuin inhibitors.