How does SIRT1 affect metabolism, senescence and cancer?

Abstract

SIRT1 is a multifaceted, NAD(+)-dependent protein deacetylase that is involved in a wide variety of cellular processes from cancer to ageing. The function of SIRT1 in cancer is complex: SIRT1 has been shown to have oncogenic properties by downregulating p53 activity, but recent studies indicate that SIRT1 acts as a tumour suppressor in a mutated p53 background, raising intriguing questions regarding its mechanism of action. Here we discuss the current understanding of how SIRT1 functions in light of recent discoveries and propose that the net outcome of the seemingly opposite oncogenic and tumour-suppressive effects of SIRT1 depends on the status of p53.

Figure 1. SIRT1 pathway overview

SIRT1 is an NAD⁺-dependent histone deacetylase that catalyses the removal of acetyl (Ac) groups from a number of non-histone targets. The downstream effects of target deacetylation include changes in cellular metabolism (lipid metabolism, insulin sensitivity, reverse cholesterol transport and gluconeogenesis) as well as cell survival and senescence effects (cell survival and DNA repair). Several protein regulators and small-molecule compounds that can activate or inhibit SIRT1 function have also been described. AROS, active regulator of SIRT1; DBC1, deleted in breast cancer 1; FOXO, forkhead box; HIC1, hypermethylated in cancer 1; LXR, liver X receptor; PGc1α, PPARγ coactivator 1α; PPARγ, peroxisome proliferator-activated receptor-γ; PTP1B, protein-tyrosine phosphatase 1B.

Figure 2. Chemotherapeutic targeting of the p53–SIRT1 pathway

a | MDM2 and SIRT1 negatively regulate p53 and prevent upregulation of p53 under normal conditions. b | Small-molecule inhibitors of MDM2 have been shown to inhibit cell growth and induce apoptosis in some tumour cell lines. c | Use of small-molecule inhibitors of SIRT1 in tumour cells that overexpress the protein may sensitize the cells to a combination of therapeutics, inducing a stronger p53 response and promoting apoptosis of tumour cells. Ac, acetyl; Ub, ubiquitin.