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| Cancer research. 2021 Mar 26. pii: 0008-5472.CAN-20-2052. doi: 10.1158/0008-5472.CAN-20-2052 |
| E2F1 and E2F2-mediated repression of CPT2 establishes a lipid-rich tumor-promoting environment. |
| Gonzalez-Romero F1, Mestre D2, Aurrekoetxea I3, O'Rourke CJ4, Andersen JB5, Woodhoo A6, Tamayo-Caro M7, Varela Rey M8, Palomo-Irigoyen M9, Gómez-Santos B10, Sáenz de Urturi D11, Núñez-García M12, García-Rodríguez JL13, Fernández-Ares L14, Buqué X15, Iglesias-Ara A16, Bernales I17, Gutierrez De Juan V18, Delgado TC19, Goikoetxea-Usandizaga N20, Lee R21, Bhanot S22, Delgado I23, Perugorria MJ24, Errazti G25, Mosteiro L26, Gaztambide S27, Martinez de la Piscina I28, Iruzubieta P29, Crespo J30, Banales JM31, Martínez-Chantar ML32, Castaño L33, Zubiaga AM34, Aspichueta P35 |
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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 involvement 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 expression was 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 fatty-acid oxidation (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. |
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Copyright ©2021, American Association for Cancer Research. |
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Publikations ID: 33771899 Quelle: öffnen |
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