Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies

Abstract

DNA methylation plays significant roles in a variety of biological and pathological processes including mammalian development, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Recent discoveries indicated that ten-eleven translocation (TET) family of dioxygenases can convert 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC). The TET family includes three members: TET1, TET2, and TET3. With increasing evidence, more and more biological and pathological processes in which 5-hmC and TET family serve unparalleled biological roles are noticed, for example, DNA demethylation and transcriptional regulation of different target genes, which are involved in many human diseases, especially hematologic malignancies, resembling chronic myelomonocytic leukemia, myelodysplastic syndromes, and so on. In this review, we focus on the diverse functions of TET family and the novel epigenetic marks, 5-mC and 5-hmC, in hematologic malignancies. This review will provide valuable insights into the potential targets of hematologic malignancies. Further understanding of the normal and pathological functions of TET family may provide new methods to develop novel epigenetic therapies for treating hematologic malignancies.

Epigenetic Regulation of p21cip1/waf1 in Human Cancer

“…So far, no clear evidence for specific histone arginine demethylases exists. Peptidylarginine deiminase 4 (PAD4) and JMJD6 have been shown to mediate arginine demethylation, but both enzymes also possess additional properties beyond demethylation [40,41].…”

Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy

“…Alternatively, ROS oxidize 5-methylcytosine to produce 5-hydroxymethylcytosine (6). This modification, mediated by the ten-eleven translocation methylcytosine dioxygenase (TET) family enzymes, is involved in the process of active demethylation of 5-hydroxymethylcytosine and is responsible for enhancing the transcriptional activity (7).…”

DNA methylation profile in patients with indolent systemic mastocytosis

“…27,28 Thus both 5-mC and 5-hmC might be involved in many biological processes such as gene-control mechanisms, and regulation of DNA methylation, and may be observed in many diseases, especially in hematologic malignancies. 10,25 The interrelation of 5-mc with 5-hmC was already described in the 90s, and demonstrated in in vitro studies in normal DNA as a response to oxidative stress. 29 5-hmC levels are decreased in various malignancies, including glioblastoma, melanoma, breast, prostate, hepatic, gastric, and renal cancers.…”

“… 9 DNA methyltransferases (DNMTs) are involved in the process of DNA methylation by catalyzing the transfer of a methyl group to the 5‐position of the cytosine in DNA and the generation of 5‐methylcytosine (5‐mC). 10 In the process of DNA demethylation, 5‐mC can be converted into 5‐hydroxymethylcytosine (5‐hmC) by TET hydroxylases, which play a key role in the active demethylation of DNA. Therefore, global DNA hypomethylation leads to chromosomal instability which may result in cell proliferation and cancer.…”