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

Hao Nie, Haixing Ju, Jiayi Fan, Xiaoliu Shi, Yaxian Cheng, Xiaohui Cang, Zhiguo Zheng, Xiaotao Duan and Wen Yi ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13601-8

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