Cell Reports (Aug 2019)
p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas
- 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
Affiliations
- Meng-Hsiung Hsieh
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Joshua H. Choe
- Department of Biological Sciences, Columbia University, New York, NY, USA
- Jashkaran Gadhvi
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Yoon Jung Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Marcus A. Arguez
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Madison Palmer
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Haleigh Gerold
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Chance Nowak
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Hung Do
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Simbarashe Mazambani
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Jordan K. Knighton
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Matthew Cha
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Justin Goodwin
- Graduate School of Art and Sciences and School of Medicine, Yale University, New Haven, CT, USA
- Min Kyu Kang
- Department of Radiation Oncology, School of Medicine, Kyungpook National University, Daegu, Korea
- Ji Yun Jeong
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
- Shin Yup Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
- Brandon Faubert
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Zhenyu Xuan
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA; Center for Systems Biology, The University of Texas at Dallas, Richardson, TX, USA
- E. Dale Abel
- Division of Endocrinology and Metabolism and the Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Claudio Scafoglio
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- David B. Shackelford
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- John D. Minna
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Pankaj K. Singh
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA
- Vladimir Shulaev
- Department of Biological Sciences, College of Science, Advanced Environmental Research Institute, University of North Texas, Denton, TX, USA
- Leonidas Bleris
- Department of Bioengineering, The University of Texas at Dallas, Richardson, TX, USA
- Kenneth Hoyt
- Department of Bioengineering, The University of Texas at Dallas, Richardson, TX, USA
- James Kim
- Department of Internal Medicine, Hamon Center for Therapeutic Oncology Research, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Masahiro Inoue
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Ralph J. DeBerardinis
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Tae Hoon Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
- Jung-whan Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA; Corresponding author
- Journal volume & issue
-
Vol. 28,
no. 7
pp. 1860 – 1878.e9
Abstract
Summary: 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. : Hsieh et al. show that p63 and SOX2 cooperate to induce enhanced GLUT1 expression, driving a critical reliance on glucose, in squamous cell carcinomas. Systemic glucose restriction by ketogenic diet or SGLT2 inhibition attenuates squamous tumor progression by disrupting redox homeostasis and insulin/AKT pathways in vivo. Keywords: p63, SOX2, GLUT1, squamous cell carcinoma, glucose restriction, ketogenic diet, SGLT2
