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González-Romero, Francisco; Mestre, Daniela; Aurrekoetxea, Igor; O'Rourke, Colm J.; Andersen, Jesper B.; Woodhoo, Ashwin; Tamayo-Caro, Miguel; Varela-Rey, Marta; Palomo-Irigoyen, Marta; Gómez-Santos, Beatriz; de Urturi, Diego Sáenz; Núñez-García, Maitane; García-Rodríguez, Juan L.; Fernández-Ares, Larraitz; Buqué, Xabier; Iglesias-Ara, Ainhoa; Bernales, Irantzu; De Juan, Virginia Gutierrez; Delgado, Teresa C.; Goikoetxea-Usandizaga, Naroa; Lee, Richard; Bhanot, Sanjay; Delgado, Igotz; Perugorria, Maria J.; [...]

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

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  • Media type: E-Article
  • Title: E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment
  • Contributor: González-Romero, Francisco; Mestre, Daniela; Aurrekoetxea, Igor; O'Rourke, Colm J.; Andersen, Jesper B.; Woodhoo, Ashwin; Tamayo-Caro, Miguel; Varela-Rey, Marta; Palomo-Irigoyen, Marta; Gómez-Santos, Beatriz; de Urturi, Diego Sáenz; Núñez-García, Maitane; García-Rodríguez, Juan L.; Fernández-Ares, Larraitz; Buqué, Xabier; Iglesias-Ara, Ainhoa; Bernales, Irantzu; De Juan, Virginia Gutierrez; Delgado, Teresa C.; Goikoetxea-Usandizaga, Naroa; Lee, Richard; Bhanot, Sanjay; Delgado, Igotz; Perugorria, Maria J.; [...]
  • Published: American Association for Cancer Research (AACR), 2021
  • Published in: Cancer Research, 81 (2021) 11, Seite 2874-2887
  • Language: English
  • DOI: 10.1158/0008-5472.can-20-2052
  • ISSN: 0008-5472; 1538-7445
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease.</jats:p> </jats:sec>
  • Access State: Open Access