POU4F1 promotes the resistance of melanoma to BRAF inhibitors through MEK/ERK pathway activation and MITF up-regulation

摘要

BRAF inhibitors (BRAFi) have shown remarkable clinical efficacy in the treatment of melanoma with BRAF mutation. Nevertheless, most patients end up with the development of BRAFi resistance, which strongly limits the clinical application of these agents. POU4F1 is a stem cell-associated transcriptional factor that is highly expressed in melanoma cells and contributes to BRAF-activated malignant transformation. However, whether POU4F1 contributes to the resistance of melanoma to BRAFi remains poorly understood. Here, we report that over-expressed POU4F1 contributed to the acquired resistance of melanoma cells to Vemurafenib. Furthermore, POU4F1 promoted the activation of ERK signaling pathway via transcriptional regulation on MEK expression. In addition, POU4F1 could increase the expression of MITF to retain the resistance of melanoma cells to BRAFi. Collectively, our findings reveal that POU4F1 re-activates the MAPK pathway by transcriptional regulation on MEK expression and promotes MITF expression, which ultimately results in the resistance to BRAFi in melanoma. Our study supports that POU4F1 is a potential combined therapeutic target with BRAFi therapy for melanoma.