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

Abstract

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

DNMT3a and TET2 in adipocyte insulin sensitivity

“…In line with these findings, Wu et al recently published work revealing a novel axis between TET2 and AMPK in the regulation of glucose homeostasis [6]. This study found that hyperglycemia destabilizes TET2 through inhibiting AMPK-mediated TET2 phosphorylation at Ser99, which leads to downregulation of global 5hmC levels in the blood of diabetic patients.…”

TET2 missense variants in human neoplasia. A proposal of structural and functional classification

“…These interactions might be regulated by phosphorylation of residue Ser99 by AMP‐activated kinase, which has been recently shown to stabilize TET2 protein. This PTM thus links hyperglycemia and diabetes to cancer through modification of the 5hmC landscape (Wu et al, ). We also note that the highly variable Asp297‐Thr395 linker is a likely major target of cysteine proteinases that regulate TET2 activity: caspases (Ko et al, ) and calpains (Wang & Zhang, ).…”

Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue

“…DNA methylation is mediated by the DNMT family, including DNMT1, DNMT3a, and DNMT3b, whereas the TET family (TET1, TET2, and TET3) catalyzes the conversion of 5‐methylcytosine to 5‐hydroxymethylcytosine to induce DNA demethylation. Previous studies revealed that hyperglycemia played a critical role in regulating the expression or activities of DNMTs and TETs (68–70). Our results indicated that mRNA expressions of Dnmts and Tets in BAT were lower at the postnatal stage compared with that at the prenatal stage, suggesting a less significant role of postnatal development in the epigenetic modification.…”