Role of ten-eleven translocation proteins and 5-hydroxymethylcytosine in hepatocellular carcinoma

Abstract

In mammals, methylation of the 5th position of cytosine (5mC) seems to be a major epigenetic modification of DNA. This process can be reversed (resulting in cytosine) with high efficiency by dioxygenases of the ten-eleven translocation (TET) family, which perform oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine. It has been demonstrated that these 5mC oxidation derivatives are in a dynamic state and have pivotal regulatory functions. Here, we comprehensively summarized the recent research progress in the understanding of the physiological functions of the TET proteins and their mechanisms of regulation of DNA methylation and transcription. Among the three TET genes, TET1 and TET2 expression levels have frequently been shown to be low in hepatocellular carcinoma (HCC) tissues and received most attention. The modulation of TET1 also correlates with microRNAs in a post-transcriptional regulatory process. Additionally, recent studies revealed that global genomic 5hmC levels are down-regulated in HCC tissues and cell lines. Combined with the reported results, identification of 5hmC signatures in HCC tissues and in circulating cell-free DNA will certainly contribute to early detection and should help to design therapeutic strategies against HCC. 5hmC might also be a novel prognostic biomarker of HCC. Thus, a detailed understanding of the molecular mechanisms resulting in the premalignant and aggressive transformation of TET proteins and cells with 5hmC disruption might help to develop novel epigenetic therapies for HCC.

Keywords: 5-hydroxymethylcytosine; TET proteins; epigenetic biomarkers; hepatocellular carcinoma; therapy and prognosis.

Figure 1

A schematic outline of the association between 5mC and 5hmC. 5mC generated from post‐duplicative transfer of the methyl group to cytosine via the catalysis by DNMTs, which utilize S‐adenosyl methionine (SAM) as a methyl donor. There are three known mammalian TET proteins at present, which catalyse the sequential oxidation of 5mC to 5hmC, 5fC and 5caC (collectively known as oxidized 5mC). Furthermore, oxygen, Fe(II) and α‐KG are indispensable for the TET enzymes to perform the successive oxidation of 5mC and of its two intermediate oxidized derivatives, 5hmC and 5fC. The final oxidized product is 5caC

Figure 2

Applications of 5hmC in circulating cell‐free DNA in the course of HCC management. Here, we present a schematic diagram for early detection of HCC by means of cell‐free DNA 5hmC. Proof‐of‐principle results indicate that cell‐free DNA 5hmC signatures are useful for early detection of HCC and evaluation of tumour stage. Large‐scale clinical trials are necessary to fully validate the feasibility and to understand potential limitations of this approach. Cell‐free DNA 5hmC constitutes a novel dimension of information for liquid biopsy‐based diagnosis and prognosis. Collectively, levels of 5hmC in cell‐free DNA can be estimated and can contribute to (a) increased understanding of molecular mechanisms; (b) HCC detection: screening or earlier diagnosis; (c) HCC patients: stratification biomarkers; (d) molecular profiling or prognostication biomarker, and (e) identification of novel therapeutic targets and monitoring response and relapse