ZMYND8-regulation of MITF as potential therapeutic target in melanoma

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Melanoma is a highly aggressive and increasingly common cancer, characterized by activating mutations in specific genes which act to activate pathways responsible for survival leading to tumor progression. Although several inhibitors have successfully entered clinical testing with remarkable effects, patients carrying the aforementioned mutations initially respond to treatment with highly effective melanoma regression, they inevitably relapse after some months. There is currently no treatment for these patients. Although a link to a protein called MITF, which acts as a master regulator of the melanoma cell phenotype has been made, the precise mechanisms underpinning MITF's control remains elusive. Despite the fact that attenuation of MITF is poorly understood, its levels have been linked to drug resistance, with low levels predicting resistance to treatment in patients carrying activating mutations in a protein called BRAF, controlling important cellular functions.This study will examine the role of a protein called ZMYND8 in affecting or controlling MITF levels in patient derived, drug resistant melanoma cell lines. We discovered that ZMYND8 acts to assemble factors that block the expression of proteins and we further found one of these factors to be directly associated with MITF expression. This project will therefore explore how the melanoma master regulator is in turn regulated, providing information on resistance versus sensitivity in melanomas. We anticipate that this research will offer new possibilities in targeting otherwise drug resistant melanomas.