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.
Highlights
Cytosine methylation (5mC) plays a vital role in development, differentiation and gene expression modulation and its mechanism of reversal were previously thought to be mediated by AID/APOBEC or by passive removal through the nuclear exclusion of DNA methyl transferase 1 (DNMT1) during replication [1,2]. 5-hydroxymethyl cytosine (5hmC) is considered as the sixth base of the genome as well as the second most significant DNA modification after 5mC [3,4]
We focus on the role of 5-hydroxymethylcytosine in cancer, cellular factors regulating its levels, mechanism of locus-specific 5hmC changes, influence of environmental factors like hypoxia, reactive oxygen species (ROS), heavy metals and carcinogens disturbing the balance between methylcytosine and hydroxymethylcytosine
Ten Eleven Translocation (TET) enzymes are known to interact with the enzyme OGT (O-GlcNAc transferase) that plays a role in chromatin modulation, O-GlcNAcylation is possible in all three TET enzymes but O-GlcNAcylation of TET3 causes TET3 nuclear export and reduces 5hmC levels in the genome [69]
Summary
Cytosine methylation (5mC) plays a vital role in development, differentiation and gene expression modulation and its mechanism of reversal were previously thought to be mediated by AID/APOBEC or by passive removal through the nuclear exclusion of DNA methyl transferase 1 (DNMT1) during replication [1,2]. 5-hydroxymethyl cytosine (5hmC) is considered as the sixth base of the genome as well as the second most significant DNA modification after 5mC [3,4]. As an individual base modification 5hmC maintenance over replication is necessary, but DNMT1 poorly methylates hemi hydroxymethylated DNA in vitro that invokes loss of maintenance of 5hmC during cell divisions [13,14]. Mutations in genes like isocitrate dehydrogenase (IDH1/2), succinate dehydrogenase (SDH) and fumarate hydratase (FH); which control 5hmC genomic levels by regulating TET activity are reported in various cancers [18,19,20]. Though mutational (IDH, SDH and FH) imbalance in methylation machinery results in the loss of 5hmC and trigger carcinogenesis, locus-specific changes of 5hmC between tumor and normal tissues is important for cancer progression. We focus on the role of 5-hydroxymethylcytosine in cancer, cellular factors regulating its levels, mechanism of locus-specific 5hmC changes, influence of environmental factors like hypoxia, reactive oxygen species (ROS), heavy metals and carcinogens disturbing the balance between methylcytosine and hydroxymethylcytosine
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