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

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.

Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Clear Cell Renal Cell Carcinoma

“…Although the E2Fs pathway is often deregulated in cancer, the roles of E2F1 as a proliferation or cell death promoter in tumorigenesis are still far from being understood [ 33 , 34 ]. Numerous studies indicate that E2F1 transcription factor is one of the most in-depth E2Fs family members in tumor research, and the high expression of E2F1 is of great significance for the poor prognosis of malignant tumors such as gastric cancer [ 35 ], hepatocellular carcinoma [ 36 ], pancreatic cancer [ 37 ], and prostate cancer [ 38 ]. Ma et al [ 9 ] have first reported that the mRNA level of E2F1 in renal clear cell carcinoma tissue is related to tumor pathological parameters, including diameter, Fuhrman tumor grade, pT staging, TNM staging and macrovascular infiltration (MAVI), and E2F1 expression with the increase of tumor tissue grade; they also found that E2F1 has promoting effects on the proliferation, migration, and invasion of cancer cells.…”

Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis

“…Chromatin immunoprecipitation (ChIP) analysis in isolated hepatocytes were performed as describe before 58 . Briefly, after hepatocytes isolation and attachment, crosslinking were directly performed on the culture plates by addition of formaldehyde to a 1% final concentration.…”

Metabolomic Characterization Reveals ILF2 and ILF3 Affected Metabolic Adaptions in Esophageal Squamous Cell Carcinoma

“…It has been reported that ILF2 can maintain mitochondrial homeostasis, especially oxidative phosphorylation, and promote the progression of small lung cancer via interacting with E2F1, which is a key transcriptional activator involved in the modulation of mitochondrial functions ( Zhao et al, 2019 ). Notably, recent studies have indicated that E2F1 and E2F2 regulate the expression of CPT2, an important enzyme for FA β-oxidation, and establish a lipid-rich environment for hepatocarcinogensis ( Gonzalez-Romero et al, 2021 ). Combined with these findings, we proposed that ILF2 might exhibit a close relationship with FA β-oxidation in ESCC.…”