摘要：SummaryMetabolic syndrome is associated with obesity, insulin resistance, and the risk of cancer. We tested whether oncogenic transcription factor c-JUN metabolically reprogrammed cells to induce obesity and cancer by reduction of glucose uptake, with promotion of the stemness phenotype leading to malignant transformation. Liquid alcohol, high-cholesterol, fat diet (HCFD), and isocaloric dextrin were fed to wild-type or experimental mice for 12 months to promote hepatocellular carcinoma (HCC). We demonstrated 40% of mice developed liver tumors after chronic HCFD feeding. Disruption of liver-specificc-Junreduced tumor incidence 4-fold and improved insulin sensitivity. Overexpression ofc-JUNdownregulatedRICTORtranscription, leading to inhibition of the mTORC2/AKT and glycolysis pathways. c-JUN inhibited GLUT1, 2, and 3 transactivation to suppress glucose uptake. Silencing of RICTOR or c-JUN overexpression promoted self-renewal ability. Taken together, c-JUN inhibited mTORC2 via RICTOR downregulation and inhibited glucose uptake via downregulation of glucose intake, leading to self-renewal and obesity.Graphical abstractDisplay OmittedHighlights•c-Jun metabolically reprograms cancer cells by disrupting insulin, mTORC2-AKT pathways•Hepatic c-Jun abundance leads to oncogenesis and insulin resistance in obesity•Reduced phosphorylation of AKT-S473 leads to insulin resistance•c-Jun represses the expression of Rictor through c-Jun binding sites of the Rictor promoterBiological sciences; Molecular biology; Endocrinology; Diabetology; Cell biology; Cancer
