The role of SIRT3, NAD-dependant deacetylases, in oral cancer carcinogenesis

Objectives: Oral cancer is the eighth most common cancer worldwide, and unfortunately, the 5-year survival rate ranges from 35%-55%. Several members of the mammalian Sirtuins (SIRT1-7), an evolutionarily conserved family of NAD-dependant deacetylases, have been purported to play an important role in carcinogenesis. SIRT1, the most characterized protein, targets several key regulators that influence carcinogenesis, including p53 and FOXO. SIRT3, another protein member of this family, was found to be associated with node-positive metastasis in breast cancer compared to normal breast tissues. Interestingly, our data show that SIRT3 is over-expressed in OSCC cells compared to normal oral human keratinocytes. Therefore, in this study our aim was to investigate whether SIRT3 over-expression plays a role in OSCC cell proliferation and survival, and whether SIRT3 can modulate the sensitivity of OSCC to anti-cancer drugs. Methods: OSCC cell lines HSC-3, UM-SCC-11A and UM-SCC-17B were used to investigate the effect of SIRT3 down-regulation in OSCC cell proliferation and survival using small interfering RNA (siRNA), analyzed by cell proliferation and cell viability assays, respectively. Cisplatin, a commonly used anti-cancer drug, was used to investigate whether SIRT3 down-regulation can increase cisplatin-induced cytotoxicity, thus affecting cell survival. Results: Down-regulation of SIRT3 inhibited cell proliferation compared to control siRNA or untreated controls. Down-regulation of SIRT3 also enhanced cisplatin-induced cytotoxicity in OSCC cells. Interestingly, the inhibition of OSCC proliferation and survival upon SIRT3 down-regulation was associated with increased p53 and Bax levels. Conclusions: Our study shows SIRT3 plays a role in OSCC carcinogenesis. The combination of cisplatin and SIRT3 down-regulation, shows promising results influencing OSCC survival. The up-regulation of p53 and Bax upon SIRT3 down-regulation may explain, in part, the inhibition on cell proliferation and survival. These findings suggest that SIRT3 may be used as a new potential therapeutic target to treat oral cancer. (NIH grant RO1DEO14429 to YLK).