c-JUN inhibits mTORC2 and glucose uptake to promote self-renewal and obesity

Raphael Serna, Ambika Ramrakhiani, Juan Carlos Hernandez, Chia Lin Chen, Chad Nakagawa, Tatsuya Machida, Ratna B. Ray, Xiaohang Zhan, Stanley M. Tahara, Keigo Machida*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Metabolic 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-specific c-Jun reduced tumor incidence 4-fold and improved insulin sensitivity. Overexpression of c-JUN downregulated RICTOR transcription, 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.

Original languageEnglish
Article number104325
Issue number6
StatePublished - 17 Jun 2022


  • Biological sciences
  • Cancer
  • Cell biology
  • Diabetology
  • Endocrinology
  • Molecular biology


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