MED15 is upregulated by HIF-2α and promotes proliferation and metastasis in clear cell renal cell carcinoma via activation of SREBP-dependent fatty acid synthesis.

Emerging evidence has highlighted that dysregulation of lipid metabolism in clear cell renal cell carcinoma (ccRCC) is associated with tumor development and progression. HIF-2α plays an oncogenic role in ccRCC and is involved in abnormal lipid accumulation. However, the underlying mechanisms between these two phenomena remain unknown. Here, MED15 was demonstrated to be a dominant factor for HIF-2α-dependent lipid accumulation and tumor progression. HIF-2α promoted MED15 transcriptional activation by directly binding the MED15 promoter region, and MED15 overexpression significantly alleviated the lipid deposition inhibition and malignant tumor behavior phenotypes induced by HIF-2α knockdown. MED15 was upregulated in ccRCC and predicted poor prognosis. MED15 promoted lipid deposition and tumor progression in ccRCC. Mechanistic investigations demonstrated that MED15 acts as SREBP coactivator directly interacting with SREBPs to promote SREBP-dependent lipid biosynthesis enzyme expression, and promotes SREBP1 and SREBP2 activation through the PLK1/AKT axis. Overall, we describe a molecular regulatory network that links MED15 to lipid metabolism induced by the SREBP pathway and the classic HIF-2α pathway in ccRCC. Efforts to target MED15 or inhibit MED15 binding to SREBPs as a novel therapeutic strategy for ccRCC may be warranted.