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AP-2alpha-mediated activation of E2F and EZH2 drives melanoma metastasis

White, J. R., Thompson, D. T., Koch, K. E., Kiriazov, B. S., Beck, A. C., van der Heide, D. M., Grimm, B. G., Kulak, M. V., Weigel, R. J.

Abstract

In melanoma metastasis, the role of the AP-2alpha transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2alpha facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2alpha interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2alpha removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment with tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable anti-metastatic effects, which were dependent on AP-2alpha. Single cell RNA-seq analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2aHigh/E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2alpha/EZH2 pathway and suggest that AP-2alpha expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas.