BRAFV600E dictates cell survival via c-Myc-dependent induction of Skp2 in human melanoma

Abstract

BRAF^V600E mutation is frequently observed in melanoma, and contributes to tumor malignancy. Despite inhibition of BRAF causes a profound cell growth inhibition and a strong clinical benefit in BRAF^V600E melanoma, acquired drug resistance is still the major hurdle. In this study, we demonstrate that BRAF^V600E drives cell growth and glycolysis in melanoma cells but does so by a previously unappreciated mechanism that involves direct induction of Skp2. Skp2 is highly expressed in melanoma tissues and particularly in tissues with BRAF^V600E mutation. The inhibition of BRAF^V600E by either siRNA or inhibitor vemurafenib suppressed Skp2 expression and cell growth. Mechanistic study shows that BRAF^V600E suppression of Skp2 is dependent on c-Myc transcription factor via specifically bounding to the E-box region on SKP2 promoter. Further, the overexpression of Skp2 resulted in a markedly increase in cell growth, cell cycle progression and glycolysis which were repressed by BRAF^V600E inhibition. Supporting the biological significance, Skp2 is specifically correlated with poor patient outcome in BRAF^V600E but did not in BRAF^WT melanomas. Thus, as a downstream target of BRAF^V600E, Skp2 is critical for responses to BRAF inhibition, indicating targeting Skp2 might be a promising strategy for the treatment of BRAFi resistant melanomas.

Keywords: BRAF(V600E); Melanoma; Skp2; Transcriptional regulation; c-Myc.