Credit: PHOTODISC

The role of SIRT1 in tumorigenesis has been at best controversial and at worst avoided altogether. Unravelling its biological function has been complicated by paradox — on the one hand, it deacetylates and thus inactivates p53, yet on the other its overexpression attenuates tumour formation in the murine Apc min/+ model. Now three recent studies place cats amongst the proverbial pigeons with data strongly implicating SIRT1 in tumour suppression.

One paper, with David Sinclair at the helm, shows that SIRT1 is recruited to sites of DNA damage following exposure to hydrogen peroxide or γ-irradiation. This implies a role for SIRT1 in the DNA repair process and, accordingly, both homologous repair and non-homologous end joining (key pathways involved in the response to double-strand breaks) were compromised following attenuation of SIRT1 activity with small interfering RNA or chemical inhibitors. Moreover, following exposure to hydrogen peroxide, SIRT1-deficient cells are particularly prone to chromosome fusions, which are indicative of defective DNA repair. Taken together, these observations argue for a role for SIRT1 in maintaining genomic stability in vitro, but can this affect tumour development in vivo? The authors conditionally overexpressed SIRT1 in both mature and progenitor lymphocytes of Trp53+/− mice and found that SIRT1 activation led to a decreased incidence of thymic lymphoma and increased survival following exposure to γ-irradiation. Collectively, these data provide tantalizing evidence that SIRT1 maintains genomic stability and suppresses tumour formation in vivo.

Another paper, spearheaded by Chu-Xia Deng, used different means to arrive at similar conclusions. The authors also found that SIRT1-deficient cells were defective in DNA repair following the generation of double- and single-stranded DNA breaks. Furthermore, they also noticed that mice that were doubly heterozygous for Sirt1 and Trp53 developed spontaneous tumours that displayed a high degree of chromosomal abnormalities yet retained a functional wild-type Sirt1 allele. Together, these results led them to conclude that SIRT1 acts to preserve genome integrity and serves as a haploinsufficient tumour suppressor protein in mice. These findings were echoed in their analysis of human tumours, in which SIRT1 levels were markedly reduced in hepatocellular and breast carcinomas — the latter providing the basis for their second study.

Here, Deng's team further delved into the mechanistic role of SIRT1 in breast cancer. Guided by the fact that decreased SIRT1 expression correlates with Brca1 mutations, they showed that BRCA1 positively regulates Sirt1 expression at both the mRNA and the protein level. Moreover, restoration of SIRT1 levels inhibited tumour formation when Brca1 mutant cells were introduced into nude mice. Accordingly, resveratrol, a SIRT1 activator, induced apoptosis in these cells. To discern how resveratrol does this, the authors examined mRNA levels for a number of genes involved in apoptosis and noticed marked downregulation of the gene that encodes the anti-apoptotic protein survivin (also known as BIRC5). Further experimental analysis showed that this suppression of survivin expression was mediated through SIRT1-dependent deacetylation of histone H3 lysine 9 at two sites within the promoter. Thus, this study points to a tripartite nexus between SIRT1, BRCA1 and survivin in breast cancer in which the tumour suppressive action of BRCA1 is at least partly mediated through SIRT1-dependent repression of survivin and, with the two other studies, provides a rationale for the use of SIRT1 activators such as resveratrol in the treatment of cancer.

Together, these three reports provide the SIRT1 community with a much needed renaissance, but whether these studies calm the waters or further ignite the SIRT1 debate will remain to be seen.