The SOX10-ACAT2-Cholesterol Synthesis Axis Is Required for Melanoma Proliferation

Research on cholesterol and its metabolic pathways has catalyzed the development of anticancer drugs targeting cholesterol synthesis. However, the cholesterol metabolic state in melanoma remains poorly characterized. In this study, we found that total cholesterol levels and the expression of acetyl-CoA acetyltransferase 2 (ACAT2), a key cholesterogenic enzyme, were significantly elevated in melanoma cells. ACAT2-mediated <i>de novo</i> cholesterol synthesis promoted melanoma growth both <i>in vitro</i> and <i>in vivo</i>. Furthermore, we identified that the transcription factor SOX10, which is critical for melanocyte development, was specifically highly expressed in melanoma and directly upregulated ACAT2 expression, thereby promoting cholesterol synthesis and tumor proliferation. Mechanistically, SOX10 transcriptionally activated ACAT2 expression by interacting with TAF15. This SOX10-TAF15 complex subsequently enhanced ACAT2 protein levels, stimulated cholesterol synthesis, suppressed apoptosis, and ultimately drove melanoma proliferation. Our findings reveal that the SOX10-TAF15-ACAT2 axis is a key regulator of cholesterol synthesis and melanoma proliferation, presenting a promising therapeutic target.