@article{dfaa584660ad4090802309c6a91253ff,
title = "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. 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 = "GLUT1, SGLT2, SOX2, glucose restriction, ketogenic diet, p63, squamous cell carcinoma",
author = "Hsieh, {Meng Hsiung} and Choe, {Joshua H.} and Jashkaran Gadhvi and Kim, {Yoon Jung} and Arguez, {Marcus A.} and Madison Palmer and Haleigh Gerold and Chance Nowak and Hung Do and Simbarashe Mazambani and Knighton, {Jordan K.} and Matthew Cha and Justin Goodwin and Kang, {Min Kyu} and Jeong, {Ji Yun} and Lee, {Shin Yup} and Brandon Faubert and Zhenyu Xuan and Abel, {E. Dale} and Claudio Scafoglio and Shackelford, {David B.} and Minna, {John D.} and Singh, {Pankaj K.} and Vladimir Shulaev and Leonidas Bleris and Kenneth Hoyt and J. Kim and Masahiro Inoue and DeBerardinis, {Ralph J.} and Kim, {Tae Hoon} and Kim, {Jung whan}",
note = "Funding Information: We thank An Hong Nguyen for technical assistance. We thank David Sidransky (Johns Hopkins University), Vlad Sandulache (Baylor College of Medicine), Ralph Weichselbaum (University of Chicago), Jeffrey Meyers (MD Anderson Cancer Center), John Minna, Richard Wang, David Wang, and Wei Zhang (University of Texas Southwestern Medical Center), and Zui Pan (University of Texas at Arlington) for providing cell lines. This work was supported by American Lung Association , United States, LCD-400239 , DOD , United States, W81XWH-18-1-0439 , CPRIT , United States, RP180670 , and NIH , United States, 5R21CA208746 and P50CA70907 to J.K.; CPRIT RP160089 and NIH R35CA220449 to R.J.D.; Japan Agency for Medical Research and Development Grants-in Aid, P-CREATE, AMED , Japan, to M.I.; NIH K25EB017222 and R01EB025841 and CPRIT RP180670 to K.H.; NIH R01CA210439 , R01CA216853 , P50CA127297 , and P01CA217798 to P.K.S.; NIH P50CA70907 to J.D.M.; American Cancer Society , United States, RSG-16-234-01-TBG to D.B.S.; NIH/ NCATS UCLA Clinical & Translational Science Institute KL2 Translational Science Award, United States, UL1TR001881 , American Cancer Society RSG-17-003-01-CCE , Tobacco-Related Disease Research Program , United States, 2016TRDRP0IR00000143977 , and STOP Cancer Foundation Seed Grant, United States, to C.S.; National Research Foundation of Korea , South Korea, NRF-2016R1A1A1A-05005315 to S.Y.L.; and NSF , United States, CAREER 1351354 and NSF 1361355 to L.B. and C.N. Funding Information: We thank An Hong Nguyen for technical assistance. We thank David Sidransky (Johns Hopkins University), Vlad Sandulache (Baylor College of Medicine), Ralph Weichselbaum (University of Chicago), Jeffrey Meyers (MD Anderson Cancer Center), John Minna, Richard Wang, David Wang, and Wei Zhang (University of Texas Southwestern Medical Center), and Zui Pan (University of Texas at Arlington) for providing cell lines. This work was supported by American Lung Association, United States, LCD-400239, DOD, United States, W81XWH-18-1-0439, CPRIT, United States, RP180670, and NIH, United States, 5R21CA208746 and P50CA70907 to J.K.; CPRIT RP160089 and NIH R35CA220449 to R.J.D.; Japan Agency for Medical Research and Development Grants-in Aid, P-CREATE, AMED, Japan, to M.I.; NIH K25EB017222 and R01EB025841 and CPRIT RP180670 to K.H.; NIH R01CA210439, R01CA216853, P50CA127297, and P01CA217798 to P.K.S.; NIH P50CA70907 to J.D.M.; American Cancer Society, United States, RSG-16-234-01-TBG to D.B.S.; NIH/NCATS UCLA Clinical & Translational Science Institute KL2 Translational Science Award, United States, UL1TR001881, American Cancer Society RSG-17-003-01-CCE, Tobacco-Related Disease Research Program, United States, 2016TRDRP0IR00000143977, and STOP Cancer Foundation Seed Grant, United States, to C.S.; National Research Foundation of Korea, South Korea, NRF-2016R1A1A1A-05005315 to S.Y.L.; and NSF, United States, CAREER 1351354 and NSF 1361355 to L.B. and C.N. Conception and design, M.H. and J.K.; Development of methodology, M.-H.H. Y.J.K, C.N. J.G. S.Y.L. V.S. P.K.S. L.B. K.H. Z.X. and M.I.; Investigation and data acquisition, M.-H.H. J.G. Y.J.K. J.H.C. M.A.A. M.P. H.G. C.N. H.D. S.M. J.K.K. M.C. M.K.K. J.Y.J. S.Y.L. B.F. and Z.X.; Data analysis and interpretation, M.-H.H. J.G. Y.J.K. J.H.C. C.N. M.C. M.K.K. J.Y.J. S.Y.L. V.S. Z.X. K.H. C.S. D.B.S. L.B. J.K. R.J.D. T.H.K. and J.K.; Technical and material support, B.F. E.D.A. J.D.M. P.K.S. J.K. M.I. R.J.D. and T.H.K.; Writing and revision of the manuscript, M.H. J.H.C. J.G. and J.K.; Study supervision, J.K. R.J.D. is an advisor for Agios Pharmaceuticals. J.D.M. receives licensing fees for lung cancer cell lines from the NCI and University of Texas Southwestern Medical Center.",
year = "2019",
month = aug,
day = "13",
doi = "10.1016/j.celrep.2019.07.027",
language = "English (US)",
volume = "28",
pages = "1860--1878.e9",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}