Melanoma is one of the deadliest form of skin cancer that can rapidly metastasize to become lethal, if not diagnosed early or left untreated. In 2016, approximately 76,380 new melanoma cases and 10,130 melanoma-related deaths are predicted in the United States. Current preventive and therapeutic strategies have not been sufficiently effective in the management of melanoma. Therefore, novel molecular targets and treatments are required for an effective management of this neoplasm. In our laboratory, we are assessing the role and functional and therapeutic significance of sirtuin family of proteins in melanoma. Sirtuins (SIRTs) have been conserved through evolution from prokaryotic to eukaryotic cells. SIRTs are nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylases and belong to class III of the histone deacetylase (HDAC) family. Seven members of the mammalian SIRT family are known to date, and despite structural similarities, each SIRT has their own biological niche, performing unique functions via regulating critical mechanisms in the cell. The role of SIRTs in cancer is somewhat controversial, as they have exhibited conflicting functions (tumor promoter vs. tumor suppressor) depending on cell and tissue contexts. The sirtuin SIRT6, a predominantly nuclear protein, has been shown to conduct ADP-ribosyl transferase and histone deacetylase activities. SIRT6 plays key roles in DNA repair, inflammation and metabolic diseases such as cancer. Currently, the role of SIRT6 in melanoma is not known. The objective of this study was to determine the role of SIRT6 in melanoma. Using a panel of human melanoma cell lines (A375, Hs 294T, G361, SK-MEL-2, SK-MEL-28, SK-MEL-31, WM115 and WM35) differing in genetic complexity and disease progression stage, and normal human epidermal melanocytes (NHEMs), we determined the endogenous expression levels of SIRT6. We found that compared to NHEMs, SIRT6 is significantly upregulated in melanoma cell lines, at mRNA as well as protein levels, as shown by quantitative Real-Time PCR and western blot analyses. Further, employing a human tissue microarray (TMA) coupled with quantitative Vectra™ analysis, we determined the expression profile of SIRT6 protein in human melanoma and melanocytic nevus tissues. Our data demonstrated that SIRT6 is significantly overexpressed in human melanoma tissues when compared to nevi. Furthermore, lentiviral short hairpin RNA-mediated knockdown of SIRT6 in human melanoma cells was found to result in a marked anti-proliferative response in melanoma cells. Taken together, our data suggest that SIRT6 overexpression could potentially be a contributing factor in melanoma progression. Further detailed studies are underway to understand the functional significance of SIRT6 in melanoma development and progression.

Citation Format: Liz Garcia-Peterson, Mary A. Ndiaye, Chandra K. Singh, Wei Huang, Nihal Ahmad. Potential pro-proliferative role of SIRT6 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 820. doi:10.1158/1538-7445.AM2017-820