Connections between TET proteins and aberrant DNA modification in cancer

• Loss-of-function mutations of TET proteins and decreased 5hmC are frequently observed in cancer.
• Numerous TET regulators influence cancer initiation and progression.
• There is a close reciprocal interplay between TET proteins and enzymes involved in cell metabolism.
• Small molecules can be exploited as modulators of TET expression and activity.

DNA methylation has been linked to aberrant silencing of tumor suppressor genes in cancer, and an imbalance in DNA methylation–demethylation cycles is intimately implicated in the onset and progression of tumors. Ten-eleven translocation (TET) proteins are Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenases that successively oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), thereby mediating active DNA demethylation. In this review, we focus on the pathophysiological role of TET proteins and 5hmC in cancer. We present an overview of loss-of-function mutations and abnormal expression and regulation of TET proteins in hematological malignancies and solid tumors, and discuss the potential prognostic value of assessing TET mutations and 5hmC levels in cancer patients. We also address the crosstalk between TET and two critical enzymes involved in cell metabolism: O-linked β-N-acetylglucosamine transferase (OGT) and isocitrate dehydrogenase (IDH). Lastly, we discuss the therapeutic potential of targeting TET proteins and aberrant DNA methylation in cancer.