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

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 Chen, Zhaoru Dong, Ruitu Lv, Yufei Xu, Mei Wang, Yong Ye, Shike Zhang, Danielle Duquette, Songmei Geng, Clark Yin, Christine Guo Lian, George F. Murphy, Gail K. Adler, Rajesh Garg, Lydia Lynch, Pengyuan Yang, Yiming Li, Fei Lan, Jia Fan, Yang Shi and Yujiang Geno Shi ()
Additional contact information
Di Wu: Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
Di Hu: Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
Hao Chen: Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
Guoming Shi: Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University
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
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
Yujiang Geno Shi: Institute of Clinical Science of Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University

Nature, 2018, vol. 559, issue 7715, 637-641

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0350-5

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