C-JUN Inhibits MTORC2 and Glucose Uptake to Promote Self-renewal and Obesity

Overview

Journal iScience

Publisher Cell Press

Date 2022 May 23

PMID 35601917

Authors

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

Soon will be listed here.

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 reduced tumor incidence 4-fold and improved insulin sensitivity. Overexpression of downregulated 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.

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