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

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  • Xiongjian Rao

    (Institute of Biochemistry, College of Life Sciences, Zhejiang University
    Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases)

  • 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
    Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases)

  • 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
    Georgia State University)

  • Yingjie Wang

    (Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
    State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Zhejiang University)

  • Binghui Shen

    (City of Hope National Medical Center)

  • Wen Yi

    (Institute of Biochemistry, College of Life Sciences, Zhejiang University
    Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases)

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.

Suggested Citation

  • 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 & Wen Yi, 2015. "O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9468
    DOI: 10.1038/ncomms9468
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    Cited by:

    1. Leandro R. Soria & Georgios Makris & Alfonso M. D’Alessio & Angela Angelis & Iolanda Boffa & Veronica M. Pravata & Véronique Rüfenacht & Sergio Attanasio & Edoardo Nusco & Paola Arena & Andrew T. Fere, 2022. "O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Fang Wu & Natali H. Muskat & Inbar Dvilansky & Omri Koren & Anat Shahar & Roi Gazit & Natalie Elia & Eyal Arbely, 2023. "Acetylation-dependent coupling between G6PD activity and apoptotic signaling," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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