Hyperglycemia Results in TET2 Destabilization to Promote Tumorigenesis

Diabetes has been linked to an increased risk of cancer, but the underlying molecular mechanism remains unknown. The TET protein family of dioxygenases (TET1, TET2, and TET3) require α-ketoglutarate to convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to facilitate DNA demethylation. Glucose availability influences α-ketoglutarate levels, prompting Wu, Hu, Chen, and colleagues to hypothesize that elevated blood glucose in patients with diabetes would result in increased 5hmC levels. Instead, 5hmC levels were reduced in peripheral blood mononuclear cells from patients with diabetes compared with healthy donors. The hyperglycemia-induced reduction in 5hmC levels required functional TET2, which is known to be a tumor suppressor. Mechanistically, TET2 was phosphorylated at serine 99 by AMPK, and this phosphorylation protected TET2 from calpain-mediated degradation. Elevated levels of glucose suppressed AMPK-mediated phosphorylation of TET2 at serine 99, resulting in TET2 destabilization and reduced 5hmC levels, suggesting that hyperglycemia may enhance tumorigenesis by promoting TET2 degradation. Consistent with these findings, high levels of glucose accelerated cell proliferation in TET2-expressing melanoma cells in vitro. In vivo, hyperglycemia promoted the growth melanoma xenografts expressing wild-type TET2 in both diabetic and nondiabetic mice, although larger tumors developed in diabetic mice. When TET2 was not expressed, larger tumors formed and there was no difference in tumor size between diabetic and nondiabetic mice. Treatment with the antidiabetic drug metformin reduced the growth of TET2-expressing tumors, but had no effect on tumors lacking TET2 expression. Altogether, these findings reveal a mechanism by which hyperglycemia can destabilize the tumor suppressor TET2 and deregulate 5hmC levels to promote tumorigenesis, providing a potential link between diabetes and cancer, and suggesting putative therapeutic targets.

Wu D, Hu D, Chen H, Shi G, Fetahu IS, Wu F, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 2018;559:637–41.

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