Cited by 477Metabolism, Diabetes, and CancerEpigenetics and DNA MethylationCancer, Hypoxia, and Metabolism

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

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Wu, Di, Hu, Di, Chen, Hao, Shi, Guoming, Fetahu, Irfete S., Wu, Feizhen, Rabidou, Kimberlie, Fang, Rui, Tan, Li, Xu, Shuyun, Liu, Hang, Argueta, Christian, Zhang, Lei, Mao, Fei, Yan, Guoquan, Chen, Jiajia, Dong, Zhaoru, Lv, Ruitu, Xu, Yufei, Wang, Mei, Ye, Yong, Zhang, Shike, Duquette, Danielle, Geng, Songmei, Yin, Clark, Lian, Christine Guo, Murphy, George F., Adler, Gail K., Garg, Rajesh, Lynch, Lydia, Yang, Pengyuan, Li, Yiming, Lan, Fei, Fan, Jia, Shi, Yang, Shi, Yujiang Geno·2018·Nature

DOI 10.1038/s41586-018-0350-5PMC PMC6430198

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Abstract

Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications 1,2. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer 3-5. 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.

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Authors: Wu, D., Hu, D., Chen, H., Shi, G., Fetahu, I. S., Wu, F., Rabidou, K., Fang, R., Tan, L., Xu, S., Liu, H., Argueta, C., Zhang, L., Mao, F., Yan, G., Chen, J., Dong, Z., Lv, R., Xu, Y., Wang, M., Ye, Y., Zhang, S., Duquette, D., Geng, S., Yin, C., Lian, C. G., Murphy, G. F., Adler, G. K., Garg, R., Lynch, L., Yang, P., Li, Y., Lan, F., Fan, J., Shi, Y., & Shi, Y. G.
Affiliations: Brigham and Women's Hospital (US)
Boston Children's Hospital (US)
Shanghai Medical College of Fudan University (CN)
Fudan University (CN)
Corresponding author: Shi, Yang
Shi, Yujiang Geno
ORCID: Wu, Di
Hu, Di
Fetahu, Irfete S.
Wu, Feizhen
Tan, Li
Xu, Shuyun
Zhang, Lei
Mao, Fei
Chen, Jiajia
Wang, Mei
Ye, Yong
Zhang, Shike
Duquette, Danielle
Geng, Songmei
Lian, Christine Guo
Adler, Gail K.
Garg, Rajesh
Lynch, Lydia
Yang, Pengyuan
Li, Yiming
Lan, Fei
Fan, Jia
Shi, Yang
Shi, Yujiang Geno
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-07
Volume: 559
Issue: 7715
Pages: 637-641
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0350-5
PMC: PMC6430198
OpenAlex: W2884558319
Cited by: 477
References: 33
Citations by year: 2026: 39 · 2025: 48 · 2024: 56 · 2023: 64 · 2022: 71 · 2021: 67 · 2020: 55 · 2019: 55 · 2018: 22
FWCI: 17.70
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (CA194302)
National Heart, Lung, and Blood Institute (T32HL007609, K24HL103845)
National Cancer Institute (R01CA194302)
National Institute of General Medical Sciences (R01GM112062)
National Institute of Allergy and Infectious Diseases (R01AI134861)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords: TET2, AMPK, hyperglycemia, diabetes mellitus, cancer, 5-hydroxymethylcytosine, DNA demethylation, protein phosphorylation, protein stability, metformin, tumor suppression, epigenetic reprogramming
MeSH terms: Adenylate Kinase, Animals, Diabetes Mellitus, DNA, DNA-Binding Proteins, Enzyme Stability, Glucose, Glycated Hemoglobin, Humans, Hyperglycemia, Metformin, Mice, Nude, Neoplasms, Phosphorylation, Phosphoserine, Proto-Oncogene Proteins, Substrate Specificity, DNA Methylation, Xenograft Model Antitumor Assays, Epigenesis, Genetic, 5-Methylcytosine, Dioxygenases, Mice

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

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