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
Affiliations
Raphael Serna
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
Ambika Ramrakhiani
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
Juan Carlos Hernandez
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
Chia-Lin Chen
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
Chad Nakagawa
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
Tatsuya Machida
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
Ratna B. Ray
Saint Louis University, Saint Louis, MO, USA
Xiaohang Zhan
Chinese Academy of Sciences and Peking Union Medical College, Beijing 100050, P.R. China
Stanley M. Tahara
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA
Keigo Machida
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA; Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA; Corresponding author
Summary: 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.
