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

Abstract

<div>Abstract<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, <i>E2f1</i> and <i>E2f2</i> expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. <i>E2f1</i><sup>−/−</sup> and <i>E2f2</i><sup>−/−</sup> mice were resistant to DEN–HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN–HFD in <i>E2f1</i><sup>−/−</sup> and <i>E2f2</i><sup>−/−</sup> mice enhanced fatty acid oxidation (FAO) and increased expression of <i>Cpt2</i>, an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following <i>E2f2</i> knockdown in liver, and overexpression of <i>E2f2</i> elicited opposing effects. E2F2 binding to the <i>Cpt2</i> promoter was enhanced in DEN–HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, <i>E2F1</i> and <i>E2F2</i> expressions inversely correlated with <i>CPT2</i> expression. Collectively, these results indicate that activation of the E2F1–E2F2–CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis.</p>Significance:<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.</p></div>

A new hope for targeted therapy of ischemia-reperfusion injury: E2F2, an important transcription factor in H/R process

“…Cpt2 is an essential enzyme in the process of fatty acid oxidation (FAO). Overexpression of E2F2 in liver cancer can bind to Cpt2 promoter and inhibit its expression, leading to abnormal lipid metabolism and promoting the progression of liver cancer [20] . However, the decrease of E2F2 expression leads to the overexpression of CPT2, and the excessive oxidation of fatty acids leads to the increase of intracellular ROS level [21] .…”