BRAF Dictates Cell Survival Via C-Myc-dependent Induction of Skp2 in Human Melanoma

BRAF 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 melanoma, acquired drug resistance is still the major hurdle. In this study, we demonstrate that BRAF 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 mutation. The inhibition of BRAF by either siRNA or inhibitor vemurafenib suppressed Skp2 expression and cell growth. Mechanistic study shows that BRAF 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 inhibition. Supporting the biological significance, Skp2 is specifically correlated with poor patient outcome in BRAF but did not in BRAF melanomas. Thus, as a downstream target of BRAF, Skp2 is critical for responses to BRAF inhibition, indicating targeting Skp2 might be a promising strategy for the treatment of BRAFi resistant melanomas.