E2F1 and E2F2-mediated repression of CPT2 establishes a lipid-rich tumor-promoting environment
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Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (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 involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also 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 with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions 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.
Original language | English |
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Journal | Cancer Research |
Volume | 81 |
Issue number | 11 |
Pages (from-to) | 2874-2887 |
Number of pages | 14 |
ISSN | 0008-5472 |
DOIs | |
Publication status | Published - 2021 |
Bibliographical note
Publisher Copyright:
© 2021 American Association for Cancer Research.
ID: 272401481