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

The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.

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

Open access

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

Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1038/s41586-018-0350-5

Cites

33 of 33 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Functions of DNA methylation: islands, start sites, gene bodies and beyond
Jones, P. A. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3230 · Cited by 6,061
Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L. M., Liu, D. R., Aravind, L., et al. (2009) · Science · doi:10.1126/science.1170116 · Cited by 5,836
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Self-citation
AMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602
Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
Self-citation
A decade of exploring the cancer epigenome—biological and translational implications
Baylin, S. B., & Jones, P. A. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3130 · Cited by 2,871
Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA
He, Y., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., et al. (2011) · Science · doi:10.1126/science.1210944 · Cited by 2,776
Diabetes and Cancer
Giovannucci, E., Harlan, D. M., Archer, M. C., Bergenstal, R. M., Gapstur, S. M., Habel, L. A., Pollak, M., Regensteiner, J. G., & Yee, D. (2010) · Diabetes Care · doi:10.2337/dc10-0666 · Cited by 2,366
Changes in diabetes-related complications in the United States, 1990-2010
Gregg, E. W., Li, Y., Wang, J., Rios Burrows, N., Ali, M. K., Rolka, D., Williams, D. E., & Geiss, L. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1310799 · Cited by 1,749
Self-citation
Long-Term Complications of Diabetes Mellitus
Nathan, D. M. (1993) · New England Journal of Medicine · doi:10.1056/nejm199306103282306 · Cited by 1,495

Show all 33 references

Sorted by citations

High-performance medicine: the convergence of human and artificial intelligence
Topol, E. J. (2019) · Nature Medicine · doi:10.1038/s41591-018-0300-7 · Cited by 10,450
Clonal hematopoiesis in human aging and disease
Jaiswal, S., & Ebert, B. L. (2019) · Science · doi:10.1126/science.aan4673 · Cited by 1,156
“However, causality could not be established, and this could represent a case of reverse causation, as hyperglycemia might influence the development or expansion of clones by interfering with TET2 function (91).”
AMP-activated protein kinase: the current landscape for drug development
Steinberg, G. R., & Carling, D. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0019-2 · Cited by 785
Overcoming cancer therapeutic bottleneck by drug repurposing
Zhang, Z., Zhou, L., Xie, N., Nice, E. C., Zhang, T., Cui, Y., & Huang, C. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00213-8 · Cited by 544
The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy
Yuan, J., Dong, X., Yap, J., & Hu, J. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00949-4 · Cited by 516
The ageing epigenome and its rejuvenation
Zhang, W., Qu, J., Liu, G.-H., & Belmonte, J. C. I. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0204-5 · Cited by 458
AMPK: restoring metabolic homeostasis over space and time
Trefts, E., & Shaw, R. J. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.015 · Cited by 478
Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention
Zhu, X., Chen, Z., Shen, W., Huang, G., Sedivy, J. M., Wang, H., & Ju, Z. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00646-9 · Cited by 425
Targeting cancer-promoting inflammation — have anti-inflammatory therapies come of age?
Hou, J., Karin, M., & Sun, B. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-00459-9 · Cited by 387
Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity
Padoan, A., Plebani, M., & Basso, D. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030676 · Cited by 366
An AMPK–caspase-6 axis controls liver damage in nonalcoholic steatohepatitis
Zhao, P., Sun, X., Chaggan, C., Liao, Z., Wong, K. I., He, F., Singh, S., Loomba, R. S., Karin, M., Witztum, J. L., et al. (2020) · Science · doi:10.1126/science.aay0542 · Cited by 312
Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential
Xu, X., Qiu, P., Jiang, X., Tan, S., Yang, Y., Yang, W., Han, Y., Chen, Y., Oyang, L., Lin, J., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01020-1 · Cited by 293
TET (Ten-eleven translocation) family proteins: structure, biological functions and applications
Zhang, X., Zhang, Y., Wang, C., & Wang, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01537-x · Cited by 297
AMPK signaling and its targeting in cancer progression and treatment
Hsu, C.-C., Peng, D., Cai, Z., & Lin, H. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.04.006 · Cited by 265
Metformin Restores Tetracyclines Susceptibility against Multidrug Resistant Bacteria
Liu, Y., Jia, Y., Yang, K., Li, R., Xiao, X., Zhu, K., & Wang, Z. (2020) · Advanced Science · doi:10.1002/advs.201902227 · Cited by 242
Metabolic rearrangements in primary liver cancers: cause and consequences
Satriano, L., Lewińska, M., Rodrigues, P. M., Bañales, J. M., & Andersen, J. B. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0217-8 · Cited by 245
Metabolic regulation of kisspeptin — the link between energy balance and reproduction
Navarro, V. M. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0363-7 · Cited by 240
SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways
Yuan, H., Han, Y., Wang, X., Li, N., Liu, Q., Yin, Y., Wang, H., Pan, L., Li, L., Song, K., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.05.022 · Cited by 211
Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing
Hua, Y., Zheng, Y., Yao, Y., Jia, R., Ge, S., & Zhuang, A. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04263-8 · Cited by 220
Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation
Zeng, Z., Xia, L., Fan, S., Zheng, J., Qin, J., Fan, X., Liu, Y., Tao, J., Liu, Y., Li, K., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.049715 · Cited by 195
Reversible histone glycation is associated with disease-related changes in chromatin architecture
Zheng, Q., Omans, N. D., Leicher, R., Osunsade, A., Agustinus, A. S., Finkin-Groner, E., D’Ambrosio, H. K., Liu, B., Chandarlapaty, S., Liu, S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09192-z · Cited by 189
Clonal hematopoiesis and non-hematologic disorders
Jaiswal, S. (2020) · Blood · doi:10.1182/blood.2019000989 · Cited by 182
Glucose Oxidase-Instructed Traceable Self-Oxygenation/Hyperthermia Dually Enhanced Cancer Starvation Therapy
He, T., Xu, H., Zhang, Y., Yi, S., Cui, R., Xing, S., Wei, C., Lin, J., & Huang, P. (2020) · Theranostics · doi:10.7150/thno.40439 · Cited by 177
Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress
Zong, Y., Zhang, C., Li, M., Wang, W., Wang, Z., Hawley, S. A., Ma, T., Feng, J.-W., Tian, X., Qu, Q., et al. (2019) · Cell Research · doi:10.1038/s41422-019-0163-6 · Cited by 168
Mechanisms that regulate the activities of TET proteins
Joshi, K., Liu, S., Breslin, P., & Zhang, J. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04396-x · Cited by 177
Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency
Chen, B., Du, Y., Zhu, H., Sun, M., Wang, C., Cheng, Y., Pang, H., Ding, G., Gao, J., Tan, Y., et al. (2022) · Nature · doi:10.1038/s41586-022-04756-4 · Cited by 162
Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality
Ramteke, P. L., Deb, A., Shepal, V., & Bhat, M. K. (2019) · Cancers · doi:10.3390/cancers11091402 · Cited by 157
Metformin, Macrophage Dysfunction and Atherosclerosis
Feng, X., Chen, W., Ni, X., Little, P. J., Xu, S., Tang, L., & Weng, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.682853 · Cited by 156
Progress in the Development of Intrinsically Conducting Polymer Composites as Biosensors
Prajapati, D. G., & Kandasubramanian, B. (2019) · Macromolecular Chemistry and Physics · doi:10.1002/macp.201800561 · Cited by 132
miR-210 transferred by lung cancer cell-derived exosomes may act as proangiogenic factor in cancer-associated fibroblasts by modulating JAK2/STAT3 pathway
Fan, J., Xu, G., Chang, Z., Zhu, L., & Yao, J. (2020) · Clinical Science · doi:10.1042/cs20200039 · Cited by 134
The function and regulation of TET2 in innate immunity and inflammation
Cong, B., Zhang, Q., & Cao, X. (2020) · Protein & Cell · doi:10.1007/s13238-020-00796-6 · Cited by 135
Overweight and obesity in pregnancy: their impact on epigenetics
Reichetzeder, C. (2021) · European Journal of Clinical Nutrition · doi:10.1038/s41430-021-00905-6 · Cited by 145
Clonal hematopoiesis: Mutation-specific adaptation to environmental change
Florez, M. A., Tran, B. T., Wathan, T. K., DeGregori, J., Pietras, E. M., & King, K. Y. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.05.006 · Cited by 129
Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes
Lopes, A. F. C. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-00976-5 · Cited by 127
Downregulation of exosomal CLEC3B in hepatocellular carcinoma promotes metastasis and angiogenesis via AMPK and VEGF signals
Dai, W., Wang, Y., Yang, T., Wang, J., Wu, W., & Gu, J. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0423-6 · Cited by 124
Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health
Kusuyama, J., Alves-Wagner, A. B., Conlin, R. H., Makarewicz, N., Albertson, B. G., Prince, N. B., Kobayashi, S., Kozuka, C., Leth‐Møller, M., Bjerre, M., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.03.004 · Cited by 116
Rising Mesopores to Realize Direct Electrochemistry of Glucose Oxidase toward Highly Sensitive Detection of Glucose
Liang, T., Zou, L., Guo, X., Ma, X., Zhang, C., Zou, Z., Zhang, Y., Hu, F., Lu, Z., Tang, K., et al. (2019) · Advanced Functional Materials · doi:10.1002/adfm.201903026 · Cited by 111
Glucose as a Major Antioxidant: When, What for and Why It Fails?
Cherkas, A., Holota, S. M., Мдзинарашвили, Т., Gabbianelli, R., & Žarković, N. (2020) · Antioxidants · doi:10.3390/antiox9020140 · Cited by 111
RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis
Zou, Z., Dou, X., Li, Y., Zhang, Z. S., Wang, J., Gao, B., Xiao, Y., Wang, Y., Zhao, L., Sun, C., et al. (2024) · Nature · doi:10.1038/s41586-024-07969-x · Cited by 97
Hydrophobic recognition allows the glycosyltransferase UGT76G1 to catalyze its substrate in two orientations
Yang, T., Zhang, J., Ke, D., Yang, W., Tang, M., Jiang, J. D., Cheng, G., Li, J., Cheng, W., Wei, Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11154-4 · Cited by 92
Combinations of histone post-translational modifications
Taylor, B. C., & Young, N. L. (2021) · Biochemical Journal · doi:10.1042/bcj20200170 · Cited by 93
The Role of Host Cell DNA Methylation in the Immune Response to Bacterial Infection
Qin, W., Scicluna, B. P., & van der Poll, T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.696280 · Cited by 91
TET methylcytosine oxidases: new insights from a decade of research
Lio, C. J., Yue, X., López-Moyado, I. F., Tahiliani, M., Aravind, L., & Rao, A. (2020) · Journal of Biosciences · doi:10.1007/s12038-019-9973-4 · Cited by 80
Atherosclerosis in diabetes mellitus: novel mechanisms and mechanism-based therapeutic approaches
Khan, A. W., & Jandeleit-Dahm, K. A. M. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-024-01115-w · Cited by 93
Metformin: A Potential Candidate for Targeting Aging Mechanisms
Hu, D., Xie, F., Xiao, Y., Chen, L., Zhong, J., Huang, D., Chen, J., Wei, J., Jiang, Y., & Zhong, T. (2021) · Aging and Disease · doi:10.14336/ad.2020.0702 · Cited by 84
Dynamic epigenetic modifications in plant sugar signal transduction
Chen, Q., Zhang, J., & Li, G. (2021) · Trends in Plant Science · doi:10.1016/j.tplants.2021.10.009 · Cited by 78
SARS-CoV-2 genomes from Saudi Arabia implicate nucleocapsid mutations in host response and increased viral load
Mourier, T., Shuaib, M., Hala, S. M., Mfarrej, S., Alofi, F. S., Naeem, R., Alsomali, A., Jorgensen, D., Subudhi, A. K., Ben-Rached, F., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28287-8 · Cited by 75
Combination of Metformin and Gefitinib as First-Line Therapy for Nondiabetic Advanced NSCLC Patients with EGFR Mutations: A Randomized, Double-Blind Phase II Trial
Li, L., Jiang, L., Wang, Y., Zhao, Y., Zhang, X., Wu, G., Zhou, X., Sun, J., Bai, J., Ren, B., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0437 · Cited by 76
Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer
Durand, J. K., Zhang, Q. H., & Baldwin, A. S. (2018) · Cells · doi:10.3390/cells7090139 · Cited by 73
The Role of DNMT Methyltransferases and TET Dioxygenases in the Maintenance of the DNA Methylation Level
Davletgildeeva, A. T., & Kuznetsov, N. A. (2024) · Biomolecules · doi:10.3390/biom14091117 · Cited by 76
DNA methylation processes in atherosclerotic plaque
Aavik, E., Babu, M., & Ylä‐Herttuala, S. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.12.006 · Cited by 72
The chromosome-level Stevia genome provides insights into steviol glycoside biosynthesis
Xu, X., Yuan, H.-Y., Yu, X., Huang, S.-Z., Sun, Y., Zhang, T., Liu, Q.-Q., Tong, H., Zhang, Y.-X., Wang, Y.-J., et al. (2021) · Horticulture Research · doi:10.1038/s41438-021-00565-4 · Cited by 61
Functional Implications of DNA Methylation in Adipose Biology
Ma, X., & Kang, S. (2019) · Diabetes · doi:10.2337/dbi18-0057 · Cited by 69
Baicalin suppresses the progression of Type 2 diabetes-induced liver tumor through regulating METTL3/m6A/HKDC1 axis and downstream p-JAK2/STAT1/clevaged Capase3 pathway
Jiang, H., Yao, Q., An, Y., Fan, L., Wang, J., & Li, H. (2021) · Phytomedicine · doi:10.1016/j.phymed.2021.153823 · Cited by 69
Catalytic flexibility of rice glycosyltransferase OsUGT91C1 for the production of palatable steviol glycosides
Zhang, J., Tang, M., Chen, Y., Ke, D., Zhou, J., Xu, X., Yang, W., He, J., Dong, H., Wei, Y., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27144-4 · Cited by 68
The magic bullet: Niclosamide
Jiang, H., Li, A. M., & Ye, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1004978 · Cited by 69
Salidroside attenuates myocardial ischemia/reperfusion injury via AMPK-induced suppression of endoplasmic reticulum stress and mitochondrial fission
Tian, X., Huang, Y., Zhang, X., Fang, R., Feng, Y., Zhang, W., Li, L., & Li, T. X. (2022) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2022.116093 · Cited by 67
The metabolic sensor AMPK: Twelve enzymes in one
Smiles, W. J., Ovens, A. J., Oakhill, J. S., & Kofler, B. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.102042 · Cited by 69
Fructose Metabolism in Tumor Endothelial Cells Promotes Angiogenesis by Activating AMPK Signaling and Mitochondrial Respiration
Fang, J., Chen, J., Zheng, J.-L., Zeng, H.-X., Chen, J.-G., Wu, C.-H., Cai, J.-L., Wang, Z., & Zhuang, S. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-1844 · Cited by 65
TET-Mediated Epigenetic Regulation in Immune Cell Development and Disease
Tsiouplis, N. J., Bailey, D. W., Chiou, L. F., Wissink, F. J., & Tsagaratou, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.623948 · Cited by 63
The functions and mechanisms of post-translational modification in protein regulators of RNA methylation: Current status and future perspectives
Chen, Y., Jiang, Z., Yang, Y., Zhang, C., Liu, H., & Wan, J. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.126773 · Cited by 62
Epigenetic regulation of cellular functions in wound healing
Pastar, I., Marjanović, J., Stone, R. C., Chen, V., Burgess, J. L., Mervis, J. S., & Tomic‐Canic, M. (2021) · Experimental Dermatology · doi:10.1111/exd.14325 · Cited by 63
The Bidirectional Relationship Between Cancer Epigenetics and Metabolism
Izzo, L., Affronti, H. C., & Wellen, K. E. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-070820-035832 · Cited by 64
Lipopolysaccharide promotes metastasis via acceleration of glycolysis by the nuclear factor-κB/snail/hexokinase3 signaling axis in colorectal cancer
Wu, X., Qian, S., Zhang, J., Feng, J., Luo, K., Sun, L., Zhao, L., Ran, Y., Sun, L., Wang, J., et al. (2021) · Cancer & Metabolism · doi:10.1186/s40170-021-00260-x · Cited by 59
Enhancement of Rebaudioside M Production by Structure-Guided Engineering of Glycosyltransferase UGT76G1
Guo, B., Deng, Z., Meng, F., Wang, Q., Zhang, Y., Yuan, Z., & Rao, Y. (2022) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c01209 · Cited by 59
Glucose metabolism controls human γδ T-cell-mediated tumor immunosurveillance in diabetes
Mu, X., Xiang, Z., Xu, Y., He, J., Lu, J., Chen, Y., Wang, X., Tu, C. R., Zhang, Y., Zhang, W., et al. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-022-00894-x · Cited by 61
Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis
Jeong, J. J., Gu, X., Nie, J., Sundaravel, S., Liu, H., Kuo, W.-L., Bhagat, T. D., Pradhan, K., Cao, J. Z., Nischal, S., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1138 · Cited by 64
TET2: A cornerstone in normal and malignant hematopoiesis
Kunimoto, H., & Nakajima, H. (2020) · Cancer Science · doi:10.1111/cas.14688 · Cited by 56
Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin
Chen, S., Zhou, X., Yang, X., Li, W., Li, S., Hu, Z., Chen, L., Shi, R., Liu, J., Chen, G., et al. (2021) · Biomolecules · doi:10.3390/biom11091373 · Cited by 58
Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia
Guan, Y., Greenberg, E. F., Hasipek, M., Shi, C., Liu, X., Kerr, C. M., Gackowski, D., Zarakowska, E., Radivoyevitch, T., Gu, X., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-01220-9 · Cited by 59
How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span
Galow, A.-M., & Peleg, S. (2022) · Cells · doi:10.3390/cells11030468 · Cited by 60
Essential Roles for the Non-Canonical IκB Kinases in Linking Inflammation to Cancer, Obesity, and Diabetes
Shin, C. H., & Choi, D. (2019) · Cells · doi:10.3390/cells8020178 · Cited by 56
Phytochemicals regulate cancer metabolism through modulation of the AMPK/PGC-1α signaling pathway
Fakhri, S., Moradi, S. Z., Moradi, S. Y., Piri, S., Varnamkhasti, B. S., Piri, S., Khirehgesh, M. R., Bishayee, A., Casarcia, N., & Bishayee, A. (2024) · BMC Cancer · doi:10.1186/s12885-024-12715-7 · Cited by 57
Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma
Jiang, H., Greathouse, R. L., Tiche, S. J., Zhao, M., He, B., Li, Y., Li, A. M., Forgo, B. L., Yip, M., Li, A., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-1029 · Cited by 50
Diabetes-Driven Atherosclerosis: Updated Mechanistic Insights and Novel Therapeutic Strategies
Karakasis, P., Theofilis, P., Patoulias, D., Vlachakis, P. K., Antoniadis, A. P., & Fragakis, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26052196 · Cited by 63
Advancements in Polymeric Nanocarriers to Mediate Targeted Therapy against Triple-Negative Breast Cancer
Fatima, M., Sheikh, A., Abourehab, M. A. S., & Kesharwani, P. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14112432 · Cited by 53
Mitochondrial and Metabolic Pathways Regulate Nuclear Gene Expression to Control Differentiation, Stem Cell Function, and Immune Response in Leukemia
Egan, G., Khan, D. H., Lee, J. B., Mirali, S., Zhang, L., & Schimmer, A. D. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1227 · Cited by 52
Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue
Heudobler, D., Rechenmacher, M., Lüke, F., Vogelhuber, M., Pukrop, T., Herr, W., Ghibelli, L., Gerner, C., & Reichle, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113540 · Cited by 50
TET2 Drives 5hmc Marking of GATA6 and Epigenetically Defines Pancreatic Ductal Adenocarcinoma Transcriptional Subtypes
Eyres, M., Lanfredini, S., Xu, H., Burns, A., Blake, A., Willenbrock, F. W., Goldin, R. D., Hughes, D. L., Hughes, S. L., Thapa, A., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.04.044 · Cited by 50
Deep Eutectic Solvents as Active Pharmaceutical Ingredient Delivery Systems in the Treatment of Metabolic Related Diseases
Huang, C., Chen, X., Wei, C., Wang, H., & Gao, H. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.794939 · Cited by 54
Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation
Zhang, T., Guan, X., Choi, U. L., Dong, Q., Lam, M. M. T., Zeng, J., Xiong, J., Wang, X., Poon, T. C. W., Zhang, H., et al. (2019) · Epigenetics & Chromatin · doi:10.1186/s13072-019-0281-x · Cited by 53
Nuclear UHRF1 is a gate-keeper of cellular AMPK activity and function
Xu, X., Ding, G., Liu, C., Ding, Y., Chen, X. L., Huang, X., Zhang, C., Lu, S., Zhang, Y., Huang, Y., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00565-y · Cited by 47
USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2
Chen, L., Smith, M. D., Lv, L., Nakagawa, T., Li, Z., Sun, S., Brown, N. G., Xiong, Y., & Xu, Y. (2020) · Science Advances · doi:10.1126/sciadv.abc9730 · Cited by 50
Dynamic regulation of epigenetic demethylation by oxygen availability and cellular redox
Lamadema, N., Burr, S., & Brewer, A. C. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.12.009 · Cited by 50
The effect of metformin on biomarkers and survivals for breast cancer- a systematic review and meta-analysis of randomized clinical trials
Zhang, Z.-J., Yuan, J., Bi, Y., Wang, C., & Liu, Y. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.01.036 · Cited by 48
The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models
Lemos, C., Schulze, V., Baumgart, S. J., Nevedomskaya, E., Heinrich, T. K., Lefranc, J., Bader, B., Christ, C. D., Briem, H., Kuhnke, L., et al. (2021) · Cellular Oncology · doi:10.1007/s13402-020-00584-8 · Cited by 48
AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis
Smith, T. K. T., Townsend, L. K., Smiles, W. J., Oakhill, J. S., Fullerton, M. D., & Steinberg, G. R. (2026) · Nature Metabolism · doi:10.1038/s42255-025-01442-3 · Cited by 55
Role of p53 Family Proteins in Metformin Anti-Cancer Activities
Yi, Y., Zhang, W., Yi, J., & Xiao, Z. J. (2019) · Journal of Cancer · doi:10.7150/jca.30659 · Cited by 47
AMP-activated protein kinase links acetyl-CoA homeostasis to BRD4 recruitment in acute myeloid leukemia
Jiang, Y., Hu, T., Wang, T., Shi, X. E., Kitano, A., Eagle, K., Hoegenauer, K. A., Konopleva, M. Y., Lin, C. Y., Young, N. L., et al. (2019) · Blood · doi:10.1182/blood.2019001076 · Cited by 47
Targeting DNA methylation and demethylation in diabetic foot ulcers
Deng, J., Wu, X., He, W., Liao, X., Tang, M., & Nie, X. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2023.01.009 · Cited by 45
Clonal haematopoiesis, ageing and kidney disease
Vlasschaert, C., Lanktree, M. B., Rauh, M. J., Kelly, T. N., & Natarajan, P. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00778-x · Cited by 42
Hyperglycemia affects global 5-methylcytosine and 5-hydroxymethylcytosine in blood genomic DNA through upregulation of SIRT6 and TETs
Yuan, E., Yang, Y., Cheng, L. Z., Deng, X., Chen, S., Zhou, X. H., & Liu, S. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0660-y · Cited by 41
Epigenetic regulation in diabetic vascular complications
Jin, J., Wang, X., Zhi, X., & Meng, D. (2019) · Journal of Molecular Endocrinology · doi:10.1530/jme-19-0170 · Cited by 44
Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by proinflammatory cytokine–induced lncRNA Morrbid
Cai, Z., Lu, X., Zhang, C., Nelanuthala, S., Aguilera, F., Hadley, A., Ramdas, B., Fang, F., Nephew, K. P., Kotzin, J. J., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci140707 · Cited by 42
Downregulation of the DNA 5-hydroxymethylcytosine is involved in mitochondrial dysfunction and neuronal impairment in high fat diet-induced diabetic mice
Liu, R., Chen, L., Wang, Z., Zheng, X., Wang, Y., Li, H., Noda, M., Liu, J., & Long, J. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.12.042 · Cited by 42
Hypoxia-Induced Senescent Fibroblasts Secrete IGF1 to Promote Cancer Stemness in Esophageal Squamous Cell Carcinoma
Ou, Z., ZHU, L. B., Chen, X., Liu, T., Cheng, G., Liu, R., Zhang, S., Tan, W., Lin, D., & Wu, C. H. (2024) · Cancer Research · doi:10.1158/0008-5472.can-24-1185 · Cited by 43
Compound C induces autophagy and apoptosis in parental and hydroquinone-selected malignant leukemia cells through the ROS/p38 MAPK/AMPK/TET2/FOXP3 axis
Chiou, J., Huang, C., Lee, Y., Wang, L., Shi, Y., Chen, Y., & Chang, L. (2020) · Cell Biology and Toxicology · doi:10.1007/s10565-019-09495-3 · Cited by 40
Insulin and Metformin Control Cell Proliferation by Regulating TDG-Mediated DNA Demethylation in Liver and Breast Cancer Cells
Yan, J.-B., Lai, C.-C., Jhu, J.-W., Gongol, B., Marin, T., Lin, S., Chiu, H.-Y., Yen, C., Wang, L.-Y., & Peng, I. (2020) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2020.06.010 · Cited by 44
Immunometabolic control of hematopoiesis
Hajishengallis, G., Li, X., & Chavakis, T. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100923 · Cited by 43
Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes
Yang, X., Cheng, Y., Zhou, J., Zhang, L., Li, X., Wang, Z., Yin, S., Zhai, L., Huang, T., Wu, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202104472 · Cited by 40

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks