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O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

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  • Hao Nie

    (Zhejiang University)

  • Haixing Ju

    (Zhejiang Cancer Hospital)

  • Jiayi Fan

    (Zhejiang University)

  • Xiaoliu Shi

    (Zhejiang University)

  • Yaxian Cheng

    (Zhejiang University)

  • Xiaohui Cang

    (Zhejiang University)

  • Zhiguo Zheng

    (Zhejiang Cancer Hospital)

  • Xiaotao Duan

    (Beijing Institute of Pharmacology and Toxicology)

  • Wen Yi

    (Zhejiang University)

Abstract

Many cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development. However, how cancer cells coordinate glucose metabolism through glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle is largely unknown. We demonstrate here that phosphoglycerate kinase 1 (PGK1), the first ATP-producing enzyme in glycolysis, is reversibly and dynamically modified with O-linked N-acetylglucosamine (O-GlcNAc) at threonine 255 (T255). O-GlcNAcylation activates PGK1 activity to enhance lactate production, and simultaneously induces PGK1 translocation into mitochondria. Inside mitochondria, PGK1 acts as a kinase to inhibit pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Blocking T255 O-GlcNAcylation of PGK1 decreases colon cancer cell proliferation, suppresses glycolysis, enhances the TCA cycle, and inhibits tumor growth in xenograft models. Furthermore, PGK1 O-GlcNAcylation levels are elevated in human colon cancers. This study highlights O-GlcNAcylation as an important signal for coordinating glycolysis and the TCA cycle to promote tumorigenesis.

Suggested Citation

  • Hao Nie & Haixing Ju & Jiayi Fan & Xiaoliu Shi & Yaxian Cheng & Xiaohui Cang & Zhiguo Zheng & Xiaotao Duan & Wen Yi, 2020. "O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13601-8
    DOI: 10.1038/s41467-019-13601-8
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    Cited by:

    1. Zhenzhen Chen & Qiankun He & Tiankun Lu & Jiayi Wu & Gaoli Shi & Luyun He & Hong Zong & Benyu Liu & Pingping Zhu, 2023. "mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Zihao Guo & Yang Zhang & Haoyue Wang & Liming Liao & Lingdi Ma & Yiliang Zhao & Ronghui Yang & Xuexue Li & Jing Niu & Qiaoyun Chu & Yanxia Fu & Binghui Li & Chuanzhen Yang, 2024. "Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. 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.
    4. Xiuxiao Tang & Pengguihang Zeng & Kezhi Liu & Li Qing & Yifei Sun & Xinyi Liu & Lizi Lu & Chao Wei & Jia Wang & Shaoshuai Jiang & Jun Sun & Wakam Chang & Haopeng Yu & Hebing Chen & Jiaguo Zhou & Cheng, 2024. "The PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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