TET proteins and epigenetic modifications in cancers

Abstract

Epigenetic modifications, including DNA methylation and histone modifications, are involved in regulation of gene expression, and alterations in these modifications are implicated in cancer onset and progression. The specific pattern of DNA methylation depends on the balance between methylation and demethylation processes. Recent studies have shown that TET proteins play a key role in DNA demethylation. TET proteins (TET1, TET2, TET3) are iron(II) and α-ketoglutarate dependent dioxygenases, and their enzymatic activity involves hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine and further to 5-formylcytosine and 5-carboxylcytosine. These modified cytosines are removed by enzymes involved in DNA repair. However, the role of TETs in gene expression regulation is not limited to their catalytic activity. TETs can interact with proteins of complexes involved in the modification of histones (i.e. EZH2, OGT, Sin3a or HCF1) and by affecting their activity and, chromatin binding ability, they can cause changes in patterns of histone methylation, acetylation and O-GlcNAcylation. There is growing evidence that decreased expression of TET proteins and mutation in TET genes are associated with cancer onset and progression.