title: O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth.
abstract: The pentose phosphate pathway (PPP) plays a critical role in macromolecule biosynthesis and maintaining cellular redox homoeostasis in rapidly proliferating cells. Upregulation of the PPP has been shown in several types of cancer. However, how the PPP is regulated to confer a selective growth advantage on cancer cells is not well understood. Here we show that glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is dynamically modified with an O-linked β-N-acetylglucosamine sugar in response to hypoxia. Glycosylation activates G6PD activity and increases glucose flux through the PPP, thereby providing precursors for nucleotide and lipid biosynthesis, and reducing equivalents for antioxidant defense. Blocking glycosylation of G6PD reduces cancer cell proliferation in vitro and impairs tumor growth in vivo. Importantly, G6PD glycosylation is increased in human lung cancers. Our findings reveal a mechanistic understanding of how O-glycosylation directly regulates the PPP to confer a selective growth advantage to tumours.
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.
authors.forename: Xiongjian
authors.initials: X
authors.lastname: Rao
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Duan
authors.affiliation: Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute, Hangzhou 310022, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Mao
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xuexia
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute, Hangzhou 310022, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute, Hangzhou 310022, China.
authors.forename: Haimiao
authors.initials: H
authors.lastname: Xu
authors.affiliation: School of Life Science and the State Key Laboratory of Microbial Technology, National Glycoengineering Research Center, Shandong University, Shandong 250100, China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: School of Life Science and the State Key Laboratory of Microbial Technology, National Glycoengineering Research Center, Shandong University, Shandong 250100, China.|Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Peng G
authors.initials: PG
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.|State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Radiation Biology, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yi
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D006031:Glycosylation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010427:Pentose Phosphate Pathway; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017382:Reactive Oxygen Species; D005954:Glucosephosphate Dehydrogenase; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D005947:Glucose; D000117:Acetylglucosamine