Melanoma, one of the deadliest cancer of skin, arises from melanocytic cells that are responsible for melanin production. Recent advances in the understanding of melanoma biology has led to the development of targeted therapies with promise. For example, BRAF inhibitors vemurafenib and dabrafenib achieved significant improvement over chemotherapy and were approved for metastatic melanomas with BRAF- mutations. More recently, the combination of dabrafenib with MEK inhibitor trametinib demonstrated improved progression-free survival, compared to monotherapy, and has received approval from the US FDA. However, even with the combination treatment, most of the patients develop acquired resistance, thereby failing to achieve lasting tumor regression. Therefore, novel target-based approaches are needed for the management of melanomas. The mammalian sirtuins constitute a family of seven known members (SIRT1 ? SIRT7) with NAD+-dependent protein deacetylase and/or ADP-ribosyltransferase activities]. In addition, they are also known to regulate post-translational acyl modifications. SIRTs play critical roles in important cellular processes, and are shown to be involved in the pathogenesis of a variety of diseases, including cancer. The role of SIRTs in cancer is extremely complex and they appears to have dichotomous functions depending on cell contexts. Among known SIRTs, SIRT3 is a mitochondrial sirtuin, which coordinates global shift in mitochondrial activity by deacetylating proteins involved in diverse mitochondrial functions. It also plays important roles in the regulation of a variety of cellular processes, including transcription, insulin secretion, and apoptosis. The fact that SIRT3 can regulate several cellular processes which are critical in cancer cell proliferation, makes it a potential therapeutic target for cancer management. While the research on the role of SIRT3 in cancer is still in its infancy, studies have suggested its tumor suppressor as well as tumor promoter roles. However, the role of SIRT3 in melanoma is not known. In our preliminary data, we have found that SIRT3 is overexpressed in melanoma and its inhibition results in a significant anti-proliferative response in melanoma cells. Further, we have also found that 4'-bromo-resveratrol (4BR), a new small molecule inhibitor of SIRT3, imparts anti- proliferative effects in human melanoma cells. Thus, based on available literature and our preliminary data, we propose to test the hypothesis that SIRT3 plays a critical role in melanoma progression via modulating p53 signaling, Ku70-Bax interaction and/or cellular metabolic homeostasis. The following specific aims are proposed: 1) o define the role of SIRT3 in melanoma development and progression, employing a tissue microarray (TMA) created from retrospective melanoma tissues from veteran patients, and an in vitro cell transformation model; 2) to define the involvement of p53 signaling, Ku70-Bax interaction, cellular metabolic homeostasis, as downstream determinants of SIRT3 in melanoma cells; and 3) to determine the therapeutic significance of SIRT3 inhibition in vivo in 1) Braf-Pten mouse melanoma mode, and patient derived xenografts (PDX) developed with prospectively collected metastatic melanoma tissues from veteran patients. We expect that the outcome of studies proposed in this application may define the role and mechanism of SIRT3 in melanocytic transformation and melanoma progression. This may ultimately lead to development of novel diagnostic, prognostic or therapeutic approaches for melanoma. Since melanoma incidence seems to be higher in the veteran population and our proposed study aimed at defining the molecular mechanism of melanoma development may lead to identification of novel strategies for the management of this deadly neoplasm. Therefore, our proposed work is relevant and significant to the health care of Veterans and is in line with the mission of the Department of Veteran Affairs.

Public Health Relevance

The goal of this study is to define the role and functional relevance of an important protein known as sirtuin3 (SIRT3) in in melanoma development and progression. This study is important because melanoma is one of the deadliest form of skin cancers. Further, several studies have found an increased risk of melanoma in Veterans. The US military currently is, and has been engaged, in missions all over the world, including recently, in the Middle EAST. Deployment to these regions is accompanied with a significant change in the climate, diet, stress and obvious exposures to war related chemicals, which impose increased risk for several diseases, including melanoma. Our study focusing on identification of new gene relevant to melanoma progression may improve therapeutic options for the management of this deadly neoplasm. Therefore, our proposed work is relevant and significant to the health care of Veterans and is in line with the mission of the Department of Veteran Affairs.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Oncology E (ONCE)
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Wm S. Middleton Memorial Veterans Hosp
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Singh, Chandra K; Chhabra, Gagan; Ndiaye, Mary Ann et al. (2018) The Role of Sirtuins in Antioxidant and Redox Signaling. Antioxid Redox Signal 28:643-661
Chhabra, Gagan; Singh, Chandra K; Ndiaye, Mary Ann et al. (2018) Prostate cancer chemoprevention by natural agents: Clinical evidence and potential implications. Cancer Lett 422:9-18
Wilking-Busch, Melissa J; Ndiaye, Mary A; Liu, Xiaoqi et al. (2018) RNA interference-mediated knockdown of SIRT1 and/or SIRT2 in melanoma: Identification of downstream targets by large-scale proteomics analysis. J Proteomics 170:99-109
Garcia-Peterson, Liz Mariely; Ndiaye, Mary Ann; Singh, Chandra K et al. (2017) SIRT6 histone deacetylase functions as a potential oncogene in human melanoma. Genes Cancer 8:701-712
Garcia-Peterson, Liz Mariely; Wilking-Busch, Melissa Jean; Ndiaye, Mary Ann et al. (2017) Sirtuins in Skin and Skin Cancers. Skin Pharmacol Physiol 30:216-224