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Review
. 2021 Jul;147(7):1869-1879.
doi: 10.1007/s00432-021-03641-3. Epub 2021 Apr 28.

Ten-eleven translocase: key regulator of the methylation landscape in cancer

Jyoti Shekhawat  1 , Kavya Gauba  1 , Shruti Gupta  1 , Bikram Choudhury  2 , Purvi Purohit  1 , Praveen Sharma  1 , Mithu Banerjee  3
Affiliations
Review

Ten-eleven translocase: key regulator of the methylation landscape in cancer

Jyoti Shekhawat et al. J Cancer Res Clin Oncol. 2021 Jul.

Abstract

Purpose: Methylation of 5th residue of cytosine in CpG island forms 5-methylcytosine which is stable, heritable epigenetic mark. Methylation levels are broadly governed by methyltransferases and demethylases. An aberration in the demethylation process contributes to the silencing of gene expression. Ten eleven translocation (TET) dioxygenase (1-3) the de novo demethylase is responsible for conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosisne (5-fC) and 5-carboxycytosine (5-caC) during demethylation process. Mutations and abnormal expression of TET proteins contribute to carcinogenesis. Discovery of TET proteins has offered various pathways for the reversal of methylation levels thus, enhancing our knowledge as to how methylation effects cancer progression.

Methods: We searched "PubMed" and "Google scholar" databases and selected studies with the following keywords "TET enzyme", "cancer", "5-hmC", and "DNA demethylation". In this review, we have discussed combinatorial use of vitamin C in inhibiting tumour growth by enhancing the catalytic activity of TET enzymes and consequently, increasing the 5-hmC levels. 5-Hydroxymethylcytosine holds promise as a prognostic biomarker in solid cancers. The contribution of induction and suppression of TET enzymes and 5-hmC carcinogenesis are discussed in haematological and solid cancers.

Results: We found that TET enzymes play central role in maintaining the methylation balance. Any anomaly in their expression may dip the balance towards cancer progression. Low levels of TET enzymes and 5-hmC correlate with tumour invasion, progression and metastasis. Also, use of vitamin C enhances TET activity.

Conclusion: TET enzymes play vital role in shaping the methylation landscape in body. 5-hmC can be used as prognostic marker in solid cancers.

Keywords: 5-Hydroxymethylcytosine; 5-Methylcytosine; Cancer; DNA demethylation; Epigenetics; TET enzymes.

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Conflict of interest statement

No.

Figures

Fig. 1
Fig. 1
a DNA methyltransferases (DNMTs) add methyl group on CpG islands of promoter regions using S-adenosylmethionine (SAM) as substrate. b During the replication process new strands are synthesized which are hemi-methylated. The hemi-methylated state is recognized by ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) and recruits DNMT1 a maintenance methyltransferase responsible for maintaining methylation of newly synthesized strands. c Failure of maintenance assembly results in reduced levels of methylation. This process of reduction of methylation levels is known as passive demethylation. d Diagrammatic representation of active DNA demethylation process performed by TET enzymes
Fig. 2
Fig. 2
Factors affecting TET enzymes activity. Mutation in isocitrate dehydrogenase (IDH) causes accumulation of 2-hydroxyglutrate (2-HG). Mutations in fumarate hydratase (FH) and succinate dehydrogenase (SDH) also inhibit activity of TET enzymes. In addition, vitamin C enhances the activity of TET enzymes
See this image and copyright information in PMC

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