Negative regulation of the deacetylase SIRT1 by DBC1

Abstract

The deacetylase SIRT1, the mammalian version of the Sir2 protein that plays a critical role in determining lifespan in yeast, has been implicated in various cellular functions and possibly in tumorigenesis and ageing. The factors regulating SIRT1 are not well known but two groups now report that the tumour suppressor DBC1 is a negative regulator of SIRT1. By inhibiting SIRT1, DBC1 promotes increased acetylation of the tumour suppressor p53 and p53-mediated apoptosis in human cells. One of two papers that show that by inhibiting the deacetylase Sirt1, DBC1 promotes increased acetylation of p53 and p53-mediated apoptosis in human cells. SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing1,2,3,4,5,6,7,8,9,10,11,12,13,14,15. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation16,17; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4–6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice10. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1α directly modulate metabolic responses1,2,3,4,5,6,7,8,9,10,11,12,13,14,15. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.