TET2 stabilization by 14-3-3 binding to the phosphorylated Serine 99 is deregulated by mutations in cancer

Dear Editor,

The Ten-Eleven Translocation-2 (TET2) gene encodes an enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the key initial step in active DNA demethylation.^1,2 TET2 and 5hmC function cooperatively as epigenetic tumor suppressors and are frequently deregulated in cancer.² We recently reported that TET2 is a bona fide substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 serine 99 (S99) at its non-catalytic N-terminal region.³ Under normal glucose conditions, this post-translational modification stabilizes the TET2 protein. Importantly, we have demonstrated that in hyperglycemic conditions, S99 phosphorylation is impaired, thereby destabilizing TET2 and inactivating its tumor suppressive function.³ These findings unveiled a “phospho-switch” that serves to regulate TET2 stability and identified a cellular pathway by which adverse extracellular signals, including high glucose, act to disable the “phospho-switch,” resulting in increased cancer risk. However, the underlying molecular mechanisms through which the S99 phospho-switch protects TET2 stability and how this regulatory mechanism is targeted by cancer mutations are still unknown.

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