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

In melanoma metastasis, the role of the AP-2 alpha 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-2 alpha facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2 alpha interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2 alpha 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 antimetastatic effects, which were dependent on AP-2 alpha. Single-cell RNA sequencing 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-2 alpha/EZH2 pathway and suggest that AP-2 alpha expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas. Significance: AP-2 alpha drives melanoma metastasis by upregulating E2F pathway genes including EZH2 through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.

Automated summary

In melanoma metastasis, the role of the transcription factor AP-2 alpha is controversial, with some studies suggesting tumor suppressor activity while others show it facilitates metastasis by upregulating E2F pathway genes including EZH2. AP-2 alpha interacts with the NuRD complex, and its loss results in removal of activating chromatin marks and promotion of metastasis. These findings suggest AP-2 alpha can serve as a biomarker for predicting response to EZH2 inhibitors in treating advanced melanomas.