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

Nature
Di WuYujiang Geno Shi

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...Continue Reading

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Citations

Aug 1, 2018·Nature Reviews. Molecular Cell Biology·Paulina Strzyz
Feb 14, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Dan-Qing YuHe-Feng Huang
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Methods Mentioned

BETA
dot blot
dot blots
immunoprecipitation
PCR
dot

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