E2F1 and E2F2-mediated repression of CPT2 establishes a lipid-rich tumor-promoting environment

Abstract

Lipid metabolism rearrangements in nonalcoholic fatty-liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocarcinogenesis (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvemnent in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expression was increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were increased and positively correlated. E2f1-/- and E2f2-/- mice were resistant to DEN-HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN-HFD in E2f1-/- and E2f2-/- mice enhanced fatty-acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for FAO whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN-HFD-administered mouse livers compared to controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expression inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1-E2F2-Cpt2 axis provides a lipid-rich environment required for hepatocarcinogenesis.