title: Connections between TET proteins and aberrant DNA modification in cancer.
abstract: 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.
authors.affiliation: La Jolla Institute, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: yun.huang@ibt.tamhsc.edu.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: La Jolla Institute, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: arao@liai.org.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics; D000077209:Decitabine; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries
chemical_list: C560974:5-carboxylcytosine; C560973:5-formylcytosine; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D000077209:Decitabine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C578792:TET3 protein, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; D015254:DNA Modification Methylases; D001374:Azacitidine
keywords: 5-hydroxymethylcytosine; 5hmC; 5mC; DNA demethylation; DNA methylation; IDH; OGT; TET; cancer