RARbeta in Melanoma: Epigenetic Regulation by Nutrients

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DESCRIPTION (provided by applicant): The incidence of melanoma is rapdily increasing in the US population. Data in the literature indicate that epigenetic changes contribute to the development and progression of melanoma. Our laboratory has generated data that suggests the retinoic acid nulcear receptor, RAR-beta2, acts a a tumor suppressor gene and that its silencing contributes to the loss of retinoic acid's ability to inhibit growth of melanoma cells. In this exploratory study, a team of scientsits with expertise in nutrition and cancer; DNA methylation; and dhromatin structure will examine RAR-beta2 promoter DNA methylation, and RAR-beta2 promoter- associated changes in histone modification and chromatin structure in normal human melanocytes and human melanoma cells having decreased expression of RAR-beta2.. Subsequently, we will measure the ability of EGCG, genistein and butyrate, alone or in combination, to alter these epigenetic modifications in the human melanoma cells. These dietary components were chosen for their reported ability to modify epigenetic changes in cancer cells. They also have been shown to inhibit the growth of some human melanoma cell lines. If these dietary constituents reverse epigenetic changes in our melanoma cell lines, we will determine if this results in the reexpression of the RAR-beta2 gene and restoration of retinoic acid induction of this gene. Lastly, we will measure the ability of EGCG, genistein and butyrate, alone or in combination to inhibit anchorage-dependent/independent growth and basement membrane invasion in our human melanoma cell lines. The dependency of these phenotypic alterations, on the ability of nutrients to cause reexpression of RARbeta2 will be tested by using siRNA to inhibit reexpression of RAR-beta2. Loss of the ability of these nutrients to alter the melanoma phenotpe in RAR-beta2 siRNA treated cells would demonstrate the requirement for RAR-beta2 reexpression. This exploratory study will provide new and potentially important data on nutrient epigenetic mechanisms in melanoma cells. Depending on results obtained, this investigation can be translated into nutritional studies with animal models of melanoma.