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

doi:10.1016/j.isci.2022.104325

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

iScience. 2022 Apr 29;25(6):104325. doi: 10.1016/j.isci.2022.104325. eCollection 2022 Jun 17.

Authors

Affiliations

¹ Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR503C, Los Angeles, CA 90033, USA.
² Saint Louis University, Saint Louis, MO, USA.
³ Chinese Academy of Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
⁴ Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.

Abstract

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.

Keywords: Biological sciences; Cancer; Cell biology; Diabetology; Endocrinology; Molecular biology.

Abstract

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