A novel SIRT2 inhibitor with p53-dependent pro-apoptotic activity in non-small-cell lung cancer [Gene Regulation]

December 30th, 2013 by Hoffmann, G., Breitenbuecher, F., Schuler, M., Ehrenhofer-Murray, A. E.

SIRT2 is an NAD+-dependent protein deacetylase whose targets include histone H4 lysine 16, p53 and α-tubulin. Since deacetylation of p53 regulates its effect on apoptosis, pharmacological inhibition of SIRT2-dependent p53 deacetylation is of great therapeutic interest for the treatment of cancer. Here, we have identified two structurally related compounds, AEM1 and AEM2, that are selective inhibitors of SIRT2 (IC50 values of 18.5 and 3.8 μM, respectively), but show only weak effects on other sirtuins like SIRT1, SIRT3 and yeast Sir2. Interestingly, both compounds sensitized non-small cell lung cancer (NSCLC) cell lines towards the induction of apoptosis by the DNA-damaging agent etoposide. Importantly, this sensitization was dependent on the presence of functional p53, thus establishing a link between SIRT2 inhibition by these compounds and p53 activation. Further, treatment with AEM1 and AEM2 led to elevated levels of p53 acetylation and to increased expression of CDKN1A, which encodes the cell cycle regulator p21WAF1, as well as the pro-apoptotic genes PUMA and NOXA, three transcriptional targets of p53. Altogether, our data suggest that inhibition of SIRT2 by these compounds causes increased activation of p53 by decreasing SIRT2-dependent p53 deacetylation. These compounds thus provide a good opportunity for lead optimization and drug development to target p53-proficient cancers.