位点特异性DNA去甲基化作为癌症表观遗传治疗的潜在靶点。

IF 3.2 Q2 GENETICS & HEREDITY
Epigenetics Insights Pub Date : 2020-10-21 eCollection Date: 2020-01-01 DOI:10.1177/2516865720964808
Sultan Abda Neja
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引用次数: 8

摘要

异常启动子DNA超甲基化是癌症的典型特征,常见于恶性肿瘤。近年来的研究表明,许多肿瘤抑制基因启动子CpG岛(CGI)上游的调控顺式元件吸引DNA甲基转移酶(DNMT),使基因高甲基化并沉默。由于表观遗传改变具有潜在的可逆性,因此它们成为有吸引力的治疗干预靶点。目前使用的地西他滨(DAC)和阿扎胞苷(AZA)是DNMT抑制剂,遵循被动去甲基化途径。然而,它们导致细胞中CpGs的全基因组去甲基化,这使得难以将其用于因果效应分析和特异性增殖的治疗。因此,通过特异性去甲基化酶进行的去甲基化对于沉默基因和修饰染色质的表观遗传重置至关重要。然而,dna结合因子可能在引导候选去甲基酶融合过程中起主要作用。在聚集调控间隔短回文重复序列(CRISPR)出现之前,锌指蛋白(ZNFs)和转录激活因子样效应蛋白(TALEs)都被用作10 - 11易位(TET)酶的结合平台,两种系统都能够在体外和体内模型中诱导靶向位点的转录。因此,位点特异性和活性去甲基化分子追踪器的发展在未来的癌症治疗中发挥着重要作用,而不仅仅是假设。因此,这篇综述是回顾新的,尽管不同的研究可能使用位点特异性去甲基化发展基于表观遗传的癌症治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Site-Specific DNA Demethylation as a Potential Target for Cancer Epigenetic Therapy.

Site-Specific DNA Demethylation as a Potential Target for Cancer Epigenetic Therapy.

Site-Specific DNA Demethylation as a Potential Target for Cancer Epigenetic Therapy.

Site-Specific DNA Demethylation as a Potential Target for Cancer Epigenetic Therapy.

Aberrant promoter DNA hypermethylation is a typical characteristic of cancer and it is often seen in malignancies. Recent studies showed that regulatory cis-elements found up-stream of many tumor suppressor gene promoter CpG island (CGI) attract DNA methyltransferases (DNMT) that hypermethylates and silence the genes. As epigenetic alterations are potentially reversible, they make attractive targets for therapeutic intervention. The currently used decitabine (DAC) and azacitidine (AZA) are DNMT inhibitors that follow the passive demethylation pathway. However, they lead to genome-wide demethylation of CpGs in cells, which makes difficult to use it for causal effect analysis and treatment of specific epimutations. Demethylation through specific demethylase enzymes is thus critical for epigenetic resetting of silenced genes and modified chromatins. Yet DNA-binding factors likely play a major role to guide the candidate demethylase enzymes upon its fusion. Before the advent of clustered regulatory interspaced short palindromic repeats (CRISPR), both zinc finger proteins (ZNFs) and transcription activator-like effector protein (TALEs) were used as binding platforms for ten-eleven translocation (TET) enzymes and both systems were able to induce transcription at targeted loci in an in vitro as well as in vivo model. Consequently, the development of site-specific and active demethylation molecular trackers becomes more than hypothetical to makes a big difference in the treatment of cancer in the future. This review is thus to recap the novel albeit distinct studies on the potential use of site-specific demethylation for the development of epigenetic based cancer therapy.

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来源期刊
Epigenetics Insights
Epigenetics Insights GENETICS & HEREDITY-
CiteScore
5.10
自引率
0.00%
发文量
10
审稿时长
8 weeks
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