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Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer

Author

Listed:
  • Di Wu

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
    Brigham and Women’s Hospital, Harvard Medical School)

  • Di Hu

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
    Brigham and Women’s Hospital, Harvard Medical School)

  • Hao Chen

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
    Boston Children’s Hospital)

  • Guoming Shi

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
    Brigham and Women’s Hospital, Harvard Medical School)

  • Irfete S. Fetahu

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Feizhen Wu

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
    Brigham and Women’s Hospital, Harvard Medical School)

  • Kimberlie Rabidou

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Rui Fang

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Li Tan

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University)

  • Shuyun Xu

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Hang Liu

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University)

  • Christian Argueta

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Lei Zhang

    (Shanghai Medical School, Fudan University)

  • Fei Mao

    (Huashan Hospital, Fudan University)

  • Guoquan Yan

    (Shanghai Medical School, Fudan University)

  • Jiajia Chen

    (Shanghai Medical School, Fudan University)

  • Zhaoru Dong

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University)

  • Ruitu Lv

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University)

  • Yufei Xu

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Mei Wang

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Yong Ye

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University)

  • Shike Zhang

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Danielle Duquette

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Songmei Geng

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Clark Yin

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Christine Guo Lian

    (Brigham and Women’s Hospital, Harvard Medical School)

  • George F. Murphy

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Gail K. Adler

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Rajesh Garg

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Lydia Lynch

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Pengyuan Yang

    (Shanghai Medical School, Fudan University)

  • Yiming Li

    (Huashan Hospital, Fudan University)

  • Fei Lan

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University)

  • Jia Fan

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University)

  • Yang Shi

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
    Boston Children’s Hospital)

  • Yujiang Geno Shi

    (Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
    Brigham and Women’s Hospital, Harvard Medical School)

Abstract

Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications1,2. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer3–5. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel ‘phospho-switch’ that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.

Suggested Citation

  • Di Wu & Di Hu & Hao Chen & Guoming Shi & Irfete S. Fetahu & Feizhen Wu & Kimberlie Rabidou & Rui Fang & Li Tan & Shuyun Xu & Hang Liu & Christian Argueta & Lei Zhang & Fei Mao & Guoquan Yan & Jiajia C, 2018. "Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer," Nature, Nature, vol. 559(7715), pages 637-641, July.
  • Handle: RePEc:nat:nature:v:559:y:2018:i:7715:d:10.1038_s41586-018-0350-5
    DOI: 10.1038/s41586-018-0350-5
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    Cited by:

    1. Yu-Jung Tseng & Yuki Kageyama & Rebecca L. Murdaugh & Ayumi Kitano & Jong Hwan Kim & Kevin A. Hoegenauer & Jonathan Tiessen & Mackenzie H. Smith & Hidetaka Uryu & Koichi Takahashi & James F. Martin & , 2024. "Increased iron uptake by splenic hematopoietic stem cells promotes TET2-dependent erythroid regeneration," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Jinzhu Zhang & Minghai Tang & Yujie Chen & Dan Ke & Jie Zhou & Xinyu Xu & Wenxian Yang & Jianxiong He & Haohao Dong & Yuquan Wei & James H. Naismith & Yi Lin & Xiaofeng Zhu & Wei Cheng, 2021. "Catalytic flexibility of rice glycosyltransferase OsUGT91C1 for the production of palatable steviol glycosides," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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