1. E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment.
- Author
-
González-Romero F, Mestre D, Aurrekoetxea I, O'Rourke CJ, Andersen JB, Woodhoo A, Tamayo-Caro M, Varela-Rey M, Palomo-Irigoyen M, Gómez-Santos B, de Urturi DS, Núñez-García M, García-Rodríguez JL, Fernández-Ares L, Buqué X, Iglesias-Ara A, Bernales I, De Juan VG, Delgado TC, Goikoetxea-Usandizaga N, Lee R, Bhanot S, Delgado I, Perugorria MJ, Errazti G, Mosteiro L, Gaztambide S, Martinez de la Piscina I, Iruzubieta P, Crespo J, Banales JM, Martínez-Chantar ML, Castaño L, Zubiaga AM, and Aspichueta P
- Subjects
- Animals, Carcinogens, Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular metabolism, Carnitine O-Palmitoyltransferase genetics, Carnitine O-Palmitoyltransferase metabolism, Diet, High-Fat adverse effects, E2F1 Transcription Factor genetics, E2F2 Transcription Factor genetics, Gene Expression Regulation, Liver Neoplasms etiology, Liver Neoplasms metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Prognosis, Promoter Regions, Genetic, Carcinoma, Hepatocellular pathology, Carnitine O-Palmitoyltransferase antagonists & inhibitors, E2F1 Transcription Factor metabolism, E2F2 Transcription Factor metabolism, Lipids analysis, Liver Neoplasms pathology, Non-alcoholic Fatty Liver Disease complications
- Abstract
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., (©2021 American Association for Cancer Research.)- Published
- 2021
- Full Text
- View/download PDF