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

iScience (Jun 2022)

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

Journal volume & issue: Vol. 25, no. 6
p. 104325

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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