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Publication : E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment.

First Author  González-Romero F Year  2021
Journal  Cancer Res Volume  81
Issue  11 Pages  2874-2887
PubMed ID  33771899 Mgi Jnum  J:306508
Mgi Id  MGI:6715704 Doi  10.1158/0008-5472.CAN-20-2052
Citation  Gonzalez-Romero F, et al. (2021) E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment. Cancer Res 81(11):2874-2887
abstractText  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. SIGNIFICANCE: These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2874/F1.large.jpg.
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