ArticleCell reports2019
p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas.
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Article in Cell reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 91 citations in OpenAlex.
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Authors and funding
31 authors at 10 institutions in 3 countries.
Meng-Hsiung HsiehDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Joshua H ChoeDepartment of Biological Sciences, Columbia University, New York, NY, USA.
Jashkaran GadhviDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Yoon Jung KimDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Marcus A ArguezDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Madison PalmerDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Haleigh GeroldDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Chance NowakDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Hung DoDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Simbarashe MazambaniDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Jordan K KnightonDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Matthew ChaDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Justin GoodwinGraduate School of Art and Sciences and School of Medicine, Yale University, New Haven, CT, USA.
Min Kyu KangDepartment of Radiation Oncology, School of Medicine, Kyungpook National University, Daegu, Korea.
Ji Yun JeongDepartment of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea.
Shin Yup LeeDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.
Brandon FaubertChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Zhenyu XuanDepartment 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 AbelDivision 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 ScafoglioDepartment of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
David B ShackelfordDepartment of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
John D MinnaHamon 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 SinghEppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA.
Vladimir ShulaevDepartment of Biological Sciences, College of Science, Advanced Environmental Research Institute, University of North Texas, Denton, TX, USA.
Leonidas BlerisDepartment of Bioengineering, The University of Texas at Dallas, Richardson, TX, USA.
Kenneth HoytDepartment of Bioengineering, The University of Texas at Dallas, Richardson, TX, USA.
James KimDepartment of Internal Medicine, Hamon Center for Therapeutic Oncology Research, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Masahiro InoueDepartment of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Ralph J DeBerardinisChildren'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 KimDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Jung-Whan KimDepartment of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA. Electronic address: jay.kim@utdallas.edu.
The University of Texas at Dallas · USKyungpook National University · KRChildren's Medical Center · USUniversity of California, Los Angeles · USColumbia University · USSouthwestern Medical Center · USUniversity of Iowa · USUniversity of Nebraska Medical Center · USUniversity of North Texas · USYale University · US
Funding
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1MUNIVERSITY OF TEXAS--SPORE IN LUNG CANCERP50CA070907 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI GIBBONS, DON LYNN · 1996 to 2024
$57.4MTissue CoreP50CA127297 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI HOLLINGSWORTH, MICHAEL A. · 2008 to 2018
$17.1MMetabolic Regulators of Tumor Growth and ProgressionR35CA220449 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI RALPH J DEBERARDINIS · 2017 to 2026
$9.4MProject 3: MUC16-Mediated Metabolic Reprograming Induces PC MetastasisP01CA217798 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI BATRA, SURINDER K. · 2018 to 2022
$8.1MInvestigating the heterogeneity of glucose transport in lung adenocarcinomaR01CA237401 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI SCAFOGLIO, CLAUDIO · 2020 to 2025
$3.1MMetabolic Regulation of Tumor Progression, Metastasis and Chemoresistance by SIRT5/ELK3 signaling in Pancreatic CancerR01CA216853 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI SINGH, PANKAJ KUMAR · 2017 to 2021
$2.6MTargeting the Metabolic Basis of Cachexia in Pancreatic CancerR01CA210439 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI SINGH, PANKAJ KUMAR · 2017 to 2021
$2.6MTargeting vismodegib-resistant tumors using BH3 mimeticsR01CA196851 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI KIM, JAMES · 2016 to 2020
$1.7M3D Super-Resolution Ultrasound Imaging for Cancer Detection and Treatment MonitoringR01EB025841 · NIBIB · UNIVERSITY OF TEXAS DALLAS · PI HOYT, KENNETH · 2019 to 2022
$1.3MMolecular Ultrasound Imaging of Cancer Response to Antiangiogenic TherapyK25EB017222 · NIBIB · UNIVERSITY OF TEXAS DALLAS · PI HOYT, KENNETH · 2014 to 2018
$804k(PQ9) Prevention of Bleomycin-induced Pulmonary Toxicity by Dichloroacetate (DCA)R21CA208746 · NCI · UNIVERSITY OF TEXAS DALLAS · PI KIM, JUNG-WHAN · 2016 to 2017
$372kNCATS NIH HHS UL1 TR001881NCI NIH HHS P01 CA217798NCI NIH HHS P50 CA070907NCI NIH HHS P50 CA127297NCI NIH HHS R01 CA196851NCI NIH HHS R01 CA210439NCI NIH HHS R01 CA216853NCI NIH HHS R01 CA237401NCI NIH HHS R21 CA208746NCI NIH HHS R21 CA212851NCI NIH HHS R35 CA220449NIBIB NIH HHS K25 EB017222NIBIB NIH HHS R01 EB025841
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.
Indexed as
Gene Expression Regulation, NeoplasticAMP-Activated Protein KinasesAnimalsApoptosisCarcinoma, Squamous CellCell ProliferationFemaleGlucoseGlucose Transporter Type 1HumansMaleMembrane ProteinsMiceMice, Inbred NODMice, KnockoutMice, SCIDAMP-Activated Protein KinasesCKAP4 protein, humanGlucoseGlucose Transporter Type 1Membrane ProteinsPhosphatidylinositol 3-KinasesProtein Serine-Threonine KinasesSlc2a1 protein, mouseSOX2 protein, humanSOXB1 Transcription FactorsStk11 protein, mouseglucose restrictionGLUT1ketogenic dietp63SGLT2SOX2squamous cell carcinoma
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