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.

Roles of ten‑eleven translocation family proteins and their O‑linked β‑N‑acetylglucosaminylated forms in cancer development (Review)

“…Epigenetic modifications, which include DNA methylation and histone modifications can alter gene expression but cannot change the primary sequence of DNA ( 8 ) Epigenetic modifications has been proven to be widely involved in tumor development ( 9 – 11 ). DNA hypermethylation is observed in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), colorectal cancer, hepatocellular carcinoma and ovarian cancer ( 12 – 14 ). TET family proteins function as DNA hydroxymethylases in vertebrates and can catalyze conversion of 5mC to 5hmC, and subsequently to 5fC and 5caC ( 15 ) ( Fig.…”

Differential expression of ten-eleven translocation genes in endometrial cancers

“…TET proteins seem to be also involved in the regulation of other epigenetic modifications, that is, the modification of histones by interacting with specific proteins responsible for these modifications and their recruitment to chromatin. 11 Reduced expression of TET at the gene and protein levels as well as changes in the level of 5-hmC is thought to be associated with the development and progression of several types of cancer, but there are no such data related to endometrial cancer.…”

DNA direct reversal repair and alkylating agent drug resistance

“…There are 9 proteins among the AlkB homologs, but the functions for most are diverse and include removal of RNA modifications [43] . Numerous protein groups use similar reaction mechanisms, which include proline hydroxylation and ten-eleven translocation [44][45][46][47] . The ALKBH reaction mechanism uses an oxidative demethylation with a Fe(II) that is coordinated to amino acids in the proteins, along with α-ketoglutarate.…”