Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Cell Prolif. 2019 Jul;52(4):e12626. doi: 10.1111/cpr.12626. Epub 2019 Apr 29.
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.
在哺乳动物中，胞嘧啶（5mC）第 5 位的甲基化似乎是 DNA 的主要表观遗传修饰。这一过程可以通过十号十一号易位（TET）家族的双加氧酶高效逆转（导致胞嘧啶），双加氧酶能将 5mC 氧化为 5-羟甲基胞嘧啶（5hmC）、5-甲酰胞嘧啶和 5-羧基胞嘧啶。已证明这些 5mC 氧化衍生物处于动态状态，并具有关键的调节功能。在这里，我们全面总结了近年来对 TET 蛋白生理功能及其调控 DNA 甲基化和转录机制的研究进展。在这三个 TET 基因中，TET1 和 TET2 的表达水平在肝细胞癌（HCC）组织中经常显示较低，受到了最多的关注。TET1 的调节也与 microRNAs 在转录后调节过程中相关。此外，最近的研究表明，HCC 组织和细胞系中的全基因组 5hmC 水平下调。结合报道的结果，在 HCC 组织和循环无细胞游离 DNA 中鉴定 5hmC 特征，肯定有助于早期检测，并有助于设计针对 HCC 的治疗策略。5hmC 也可能是 HCC 的一种新的预后生物标志物。因此，详细了解导致 TET 蛋白和具有 5hmC 破坏的细胞发生癌前和侵袭性转化的分子机制，可能有助于开发针对 HCC 的新型表观遗传疗法。
