p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas.

Abstract

Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors. Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. Furthermore, reduction of blood glucose lowers blood insulin levels, which suppresses PI3K/AKT signaling in SCC cells. Clinically, we demonstrate a robust correlation between blood glucose concentration and worse survival among SCC patients. Collectively, this study identifies the exceptional glucose reliance of SCC and suggests its candidacy as a highly vulnerable cancer type to be targeted by systemic glucose restriction.

• Authors: Meng-Hsiung Hsieh, Joshua H Choe, Jashkaran Gadhvi, Yoon Jung Kim, Marcus A Arguez, Madison Palmer, Haleigh Gerold, Chance Nowak, Hung Do, Simbarashe Mazambani, Jordan K Knighton, Matthew Cha, Justin Goodwin, Min Kyu Kang, Ji Yun Jeong, Shin Yup Lee, Brandon Faubert, Zhenyu Xuan, E Dale Abel, Claudio Scafoglio, David B Shackelford, John D Minna, Pankaj K Singh, Vladimir Shulaev, Leonidas Bleris, Kenneth Hoyt, James Kim, Masahiro Inoue, Ralph J DeBerardinis, Tae Hoon Kim, Jung-Whan Kim
• Journal: Cell reports (Cell Rep) Vol. 28 Issue 7 Pg. 1860-1878.e9 (08 13 2019) ISSN: 2211-1247 [Electronic] United States
• PMID: 31412252 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• CKAP4 protein, human
• Glucose Transporter Type 1
• Membrane Proteins
• SOX2 protein, human
• SOXB1 Transcription Factors
• Slc2a1 protein, mouse
• Protein Serine-Threonine Kinases
• Stk11 protein, mouse
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases
• Animals
• Apoptosis
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Glucose (metabolism)
• Glucose Transporter Type 1 (physiology)
• Humans
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Serine-Threonine Kinases (physiology)
• SOXB1 Transcription Factors (genetics, metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays