TAF3 Promotes Tumor Progression of Hepatocellular Carcinoma via SREBP2-mediated Cholesterol Synthesis Pathway Activation

ABSTRACT: Our prior work identified TATA-binding protein-associated factor 3 (TAF3) as a key prognostic marker in hepatocellular carcinoma (HCC). Here, we investigate TAF3’s functional role and mechanistic basis in HCC progression. Loss- and gain-of-function assays demonstrated that TAF3 significantly altered proliferation, invasion, and migration in HepG2 and MHCC97H cell lines. Clinical analysis of 30 HCC specimens revealed that elevated TAF3 expression correlated strongly with larger tumor size, increased tumor number, microvascular invasion, advanced stage, poor differentiation, and worse prognosis. Mechanistically, comprehensive ChIP-seq and luciferase reporter assays identified sterol regulatory element-binding protein 2 (SREBP2) as a direct transcriptional target of TAF3. TAF3 bound the SREBP2 promoter, upregulating its expression and activating cholesterol biosynthesis. TAF3’s oncogenic effects were cholesterol-dependent, as cholesterol supplementation rescued malignant phenotypes in TAF3-deficient cells. Our findings establish that TAF3 drives HCC progression via SREBP2-mediated cholesterol biosynthesis, providing insights into the metabolic basis of HCC aggressiveness. These results elucidate a transcriptional-metabolic axis in HCC and suggest therapeutic potential in TAF3-overexpressing tumors with vascular invasion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306284 | GEO | 2026/09/09

REPOSITORIES: GEO