Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

Abstract

Epigenetic modes of gene regulation are important for physiological conditions and its aberrant changes can lead to disease like cancer. 5-hydroxymethylcytosine (5hmC) is an oxidized form of 5-methylcytosine (5mC) catalyzed by Ten Eleven Translocation (TET) enzymes. 5hmC is considered to be a demethylation intermediate and is emerging as a stable and functional base modification. The global loss of 5hmC level is commonly observed in cancers and tumorigenic germline mutations in IDH, SDH and FH are found to be inhibiting TET activity. Although a global loss of 5hmC is characteristic in cancers, locus-specific 5hmC gain implicates selective gene expression control. The definitive role of 5hmC as a tumor suppressing or promoting modification can be deduced by identifying locus-specific 5hmC modification in different types of cancer. Determining the genes carrying 5hmC modifications and its selective variation will open up new therapeutic targets. This review outlines the role of global and locus-specific changes of 5hmC in cancers and the possible mechanisms underlying such changes. We have described major cellular factors that influence 5hmC levels and highlighted the significance of 5hmC in tumor micro environmental condition like hypoxia.

The Role of Ten-Eleven Translocation Proteins in Inflammation

“…Hydrogen sulfide derived from the metabolism of methionine has shown to lead to sulfhydration of the transcriptional activator nuclear transcription factor Y subunit beta (NFYB), resulting in increased transcription of TET1 and TET2 ( 170 ). Post-translational modification of TET enzymes, including O-linked-N-acetylglucosamine (O-GlcNAc) Transferase, phosphorylation, Poly-Adenosine Ribosylation (PARylation) and monoubiquitination have shown to significantly affect their enzymatic activity and stability ( 171 ). Although TET deficiency enhances cell survival and increases cell “stemness”, recent studies discuss the possibility of temporarily inhibiting TET activity in order to enhance immune responses.…”

5-Methylcytosine and 5-Hydroxymethylcytosine Signatures Underlying Pediatric Cancers

“…An elevated global level of 5mC and 5hmC has been reported in mixed-lineage leukemia (MLL), acute myeloid leukemia [ 21 ], and breast cancer [ 22 ]. Moreover, aberrations in cofactor biochemical pathways involving 2-oxoglutarate, together with mutations in IDH1/2 [ 23 ], SDH , and FH [ 24 ] may alter levels of 5hmC and 5mC in certain types of tumors, in either a direct or indirect manner [ 25 ]. To shed light on recent developments on pediatric cancer predisposition and tumor progression, here we discuss the role of genome-wide and locus-specific dysregulation of 5mC and 5hmC in the most common type of pediatric cancer, i.e., hematopoiesis malignancy and neuroblastoma, together with their therapeutic potential.…”

Epigenetic DNA Modifications Are Correlated With B Chromosomes and Sex in the Cichlid Astatotilapia latifasciata

“…Deregulation of Dnmt, Tet, and Tdg activity can change the pattern of DNA epimarks, and this can result in disturbances of the transcriptional or posttranscriptional mechanisms that regulate the expression of the dnmt, tet , and tdg genes (Denis et al, 2011; Arvinden et al, 2017). Among these mechanisms, the action of microRNAs (miRNA) is widely recognized (Kuc et al, 2017).…”