AP-2α–Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis

Abstract

In melanoma metastasis, the role of the AP-2α transcription factor, which is encoded by <i>TFAP2A</i>, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high <i>TFAP2A</i> expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2α facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including <i>EZH2</i>. A BioID screen found that AP-2α interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2α removed activating chromatin marks in the promoters of <i>EZH2</i> 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 antimetastatic effects, which were dependent on AP-2α. Single-cell RNA sequencing analysis of a metastatic melanoma mouse model revealed hyperexpansion of <i>Tfap2a</i> ^High/E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2α/EZH2 pathway and suggest that AP-2α expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas. SIGNIFICANCE: AP-2α drives melanoma metastasis by upregulating E2F pathway genes including <i>EZH2</i> through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.