Abstract LB-209: SIRT3, a mitochondrial sirtuin deacetylase, promotes survival of human melanoma cells.

Abstract

Abstract Melanoma is one of the most aggressive skin cancers and is often lethal, if not diagnosed early. The existing therapeutic approaches as well as preventive strategies have not been able to effectively manage melanoma. A better understanding of mechanisms of melanoma development and progression may lead to additional means for the management of this deadly neoplasm. Sirtuins are NAD+-dependent protein deacetylases and mono-[ADP-ribosyl]transferases, which have been shown to regulate metabolism, stress responses, and longevity, in model organisms. Mammalian sirtuins, also referred to as class III histone deacetylases, have seven members (SIRT1-7) that differ widely in their localization, activity, and functions. The role of sirtuins in cancer is extremely complex and they have been shown to exhibit dichotomous functions (tumor promoter versus tumor suppressor) depending on cell contexts. SIRT3 is a mitochondrial deacetylase that regulates the activity of enzymes to coordinate global shifts in cellular metabolism. While studies have suggested that the SIRT3 acts as a tumor suppressor in some cancers (such as breast cancer), the tumor promoter function of SIRT3 has also been reported in other cancers (such as oral squamous cell carcinoma). The objective of this study was to determine the role of the SIRT3 in melanoma. Employing a panel of human melanoma cell lines (SK-MEL-28, WM35 and G361) and normal human epidermal melanocytes (NHEMs), we determined the endogenous levels of SIRT3. We found that compared to NHEMs, SIRT3 is significantly upregulated in human melanoma cells, at mRNA as well as protein levels, as shown by quantitative Real-Time PCR and Western blot analysis, respectively. Further, employing a tissue microarray (TMA) analysis, we determined the expression profile of SIRT3 protein in clinical melanoma and normal skin tissues. We found that SIRT3 is overexpressed in human melanoma, when compared to normal skin. Further, we determined the effect of a short hairpin RNA (shRNA)-mediated RNA interference on melanoma cells. Our data demonstrated that shRNA knockdown of SIRT3 resulted in a significant decrease in the growth, viability and clonogenic survival of human melanoma cells. Taken together, our data suggested that i) SIRT3 overexpression could be a contributing factor in melanoma survival, and ii) SIRT3 could serve as a potential target towards developing novel strategies for the management of melanoma. However, further in-depth studies are needed to determine the functional significance of SIRT3 overexpression in melanoma development and progression. Citation Format: Jasmine George, Minakshi Nihal, Chandra K. Singh, Nihal Ahmad. SIRT3, a mitochondrial sirtuin deacetylase, promotes survival of human melanoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-209. doi:10.1158/1538-7445.AM2013-LB-209