Melanoma, a potentially lethal form of skin cancer, is the fifth most common type of new cancer diagnosis in American men and the sixth most common type in American women. Alarmingly, the annual incidence of melanoma among whites has increased steadily (>60% over the past 30 years). Despite new developments in therapy, the overall survival of patients with advance-stage melanoma has not significantly improved. Therefore, concerted mechanism-based efforts are needed for prevention, diagnosis and treatment of this deadly neoplasm. A better understanding of molecular mechanisms contributing to melanoma development and progression can be useful in crafting new strategies for melanoma management. We are studying the role of sirtuin family of proteins in melanoma development and progression. Mammalian sirtuins (SIRT 1-7) are nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, which have been shown to regulate metabolism, stress responses, and longevity, in model organisms. The role of sirtuins in cancer is fairly complex with dichotomous functions (tumor promoter versus tumor suppressor) depending on cell contexts. SIRT3 is a mitochondrial deacetylase that has been shown to be important in maintaining cellular metabolism by regulating mitochondrial functions. We have previously shown that SIRT3 was overexpressed in human melanoma cells and tissues and its inhibition resulted in an antiproliferative response in human melanoma cells (In: AACR Annual Meeting: Proceedings; 2013 April 6-April 10, Washington, DC; Abstract # 13-LB-9391). In this study, we found that short hairpin RNA (shRNA)-mediated knockdown of SIRT3 in SK-MEL-28 melanoma cells resulted in 1) G1-phase arrest of cell cycle, 2) induction of senescence as assessed by increase in senescence-associated β-galactosidase (SA-β-gal) activity, 3) senescence associated hetrochromatin formation (SAHF), 4) decrease in cell migration, and 5) increase in protein levels of p53, phospho-p53 (Ser15), p21Waf1, pRb and p16INK4a. Further, a stable exogenous overexpression of SIRT3 resulted in an increase in cell growth and clonogenic survival in Hs 294T melanoma cells. Based on our data we suggest that SIRT3 could be a contributing factor in melanoma survival. However, further extensive in-vitro and in- vivo studies are needed to ascertain the functional significance of SIRT3 in melanoma development and progression.

Citation Format: Jasmine George, Minakshi Nihal, Chandra K. Singh, Weixiong Zhong, Nihal Ahmad. The mitochondrial sirtuin SIRT3 promotes survival of human melanoma cells in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3516. doi:10.1158/1538-7445.AM2014-3516