O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth

Xiongjian Rao, Xiaotao Duan, Weimin Mao, Xuexia Li, Zhonghua Li, Qian Li, Zhiguo Zheng, Haimiao Xu, Min Chen, Peng G. Wang, Yingjie Wang, Binghui Shen and Wen Yi ()
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Xiongjian Rao: Institute of Biochemistry, College of Life Sciences, Zhejiang University
Xiaotao Duan: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology
Weimin Mao: Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute
Xuexia Li: Institute of Biochemistry, College of Life Sciences, Zhejiang University
Zhonghua Li: Institute of Biochemistry, College of Life Sciences, Zhejiang University
Qian Li: Institute of Biochemistry, College of Life Sciences, Zhejiang University
Zhiguo Zheng: Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute
Haimiao Xu: Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute
Min Chen: School of Life Science and the State Key Laboratory of Microbial Technology, National Glycoengineering Research Center, Shandong University
Peng G. Wang: School of Life Science and the State Key Laboratory of Microbial Technology, National Glycoengineering Research Center, Shandong University
Yingjie Wang: Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
Binghui Shen: City of Hope National Medical Center
Wen Yi: Institute of Biochemistry, College of Life Sciences, Zhejiang University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9468

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