Role of sirtuin 6 in melanoma development and progression

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Melanoma incidences are increasing rapidly with 100,350 cases predicted in 2020 in the US. Further, melanoma is a significant problem in Veterans, and it is among the five most frequently diagnosed cancers among VA cancer patients. Malignant melanoma is one of the deadliest forms of cancer, and the existing therapeutics, including recently approved BRAF inhibitors, have not been fully effective in melanoma management due to acquired resistance. Therefore, novel target-based approaches are needed for the management of this neoplasm. We have an ongoing research program to define the role of sirtuins in melanoma. The mammalian sirtuins constitute a family of seven members (SIRT1 – SIRT7), which play critical roles in important cellular processes, and are involved in a variety of diseases, including cancer. The role of SIRTs in cancer is complex, and they appear to have dichotomous functions depending on cell context. Recent studies have implicated sirtuin 6 (SIRT6), a predominantly nuclear protein, in regulating pathways involved in gene transcription, glucose homeostasis, DNA repair and telomere integrity. SIRT6 has been found to suppress tumorigenesis in the intestine and liver. However, SIRT6 also has a pro-proliferative role in skin and prostate cancer, suggesting that its function may be tissue- and context- dependent. Interestingly, SIRT6 has also been shown to modulate epithelial-mesenchymal transition (EMT) and promote metastasis in certain cancer types. In a recent study, we have demonstrated that SIRT6 is overexpressed in human melanoma cells and tissues, and SIRT6 inhibition via shRNA-mediated RNA interference resulted in a marked antiproliferative response (growth inhibition, cell cycle alternation, inhibition of cell migration, senescence and autophagy dysregulation) in melanoma cells. Our preliminary data and published study together with other published research provide a strong scientific premise to our investigation into the role and potential therapeutic significance of SIRT6 in melanoma and supports our proposed hypothesis that SIRT6 plays a critical role in melanocytic transformation and melanoma progression and together with other driver pathways, can be therapeutically exploited for melanoma management. The following specific aims are proposed: 1) To define the role of SIRT6 in melanoma development and progression and its association with critical melanoma driver pathways employing a tissue microarray (TMA) created from retrospective melanoma tissues from Veteran patients. In this aim, we will determine the role of SIRT6 in melanoma as well as its association with critical melanoma driver pathways (RAS/RAF/MEK/ERK-, and p16/cyclin D-CDK4/6-RB- pathways); 2) To determine the functional and mechanistic significance of SIRT6 in melanoma. In this aim, we will determine the effect of CRISPR/Cas9 mediated SIRT6 deletion on growth and progression of melanoma cells in vitro and in vivo; and 3) To determine the therapeutic significance of SIRT6 inhibition alone and in combination with other promising target-based anti-melanoma modalities in vivo. We will determine the effects of SIRT6 inhibition using small molecule SIRT6 inhibitor alone and in combination with other clinically relevant melanoma therapies (BRAF inhibitor, Vemurafenib; and MEK inhibitor, Trametinib) on melanoma development, growth and metastasis in 1) Braf-Pten mouse model, and 2) patient-derived xenografts (PDX). We expect that our study will define the role, mechanism, and interactions of SIRT6 in melanoma as well as novel combinations in pre-clinical settings, which could be useful for future clinical investigations. This may ultimately lead to the development of novel diagnostic, prognostic, and therapeutic approaches for melanoma. Hence, our proposed study is relevant and significant to the health care of Veterans and is in line with the mission of the Department of Veteran Affairs.