DNA 甲基转移酶在肿瘤发病机制中的研究进展

DNA甲基化是表观遗传学的主要形式,而DNA甲基转移酶（ DNMTs）是DNA甲基化的主要调节酶,DNA甲基转移酶的激活参与了肿瘤的发生和发展过程,同时伴有肿瘤抑制基因的高甲基化沉默和低表达,是病人预后不良的标志;DNA甲基转移酶3b（ DNMT3b）的多态性及吸烟所致的DNMTs表达的改变是肿瘤发生的危险因素,靶向DNMTs治疗由于其细胞毒性小,是当前研究的一个热点。本文就DNA甲基转移酶在肿瘤发病机制中的作用做一综述。     

基因甲基化研究概述

表观遗传学(epigenetics)反映的主要是基因型和表型的关系。研究范围包括:DNA甲基化、组蛋白修饰、染色体重塑、遗传印记、X染色体失活、RNA调控、转座元件、副突变、位置效应斑、等位反式互补等[1～5]。近年来研究较多的是胞嘧啶DNA甲基化、RNA干扰(RNAi)调控、组蛋白修饰3种,尤其是DNA甲基化。2003年欧洲HEC宣布实施人类表观基因组计划(HEP),以指导和系统地研究DNA基因甲基化在人类表观遗传、胚胎发育、基因印记、等位基因失活及肿瘤发生中的作用[6]。本文就现阶段对DNA甲基化研究的基本现状作一概述,以获得1个整体认识,从而在此基础上对其作进一步研究。1CpG岛DNA甲基化多发生于DNA链上胞嘧啶第5位碳原子,其与甲基共价结合,胞嘧啶由此被修饰为5甲基胞嘧啶(5mC),哺乳动物基因组中5mC占胞嘧啶总量的2%～7%,70%～90%的5mC存在于CG二联核苷。CG在DNA中呈回文结构,通常称为CpG(p表示磷酸基),中文为磷酸胞苷酰[7]。哺乳动物中,CpG序列在基因组中出现的频率仅有1%,远低于基因组中的其它双核苷酸序列。但在基因组的某些区域中,CpG序列密度很高,可以达均值的5倍以上...     

DNA甲基化与大肠癌发生的研究进展

DNA甲基化由于影响基因突变、基因表达调控、基因组稳定性等方面 ,因此在肿瘤的发生和演进过程中扮演着一定的角色。近来 ,DNA甲基化机制及其与大肠癌发生关系的研究进展很快 ,现对最近 3年这方面的进展作一简要介绍。1　 DNA甲基化的概念DNA甲基化主要指在胞嘧啶的 5位碳上加上一个甲基基团 ,该反应由 S-腺苷蛋氨酸 (SAM)提供甲基 ,由 DNA甲基转移酶 (DMT)催化 ,形成 5甲基胞嘧啶 (5 m C)。 5 m C是真核细胞中唯一天然存在的修饰碱基 ,约占整个胞嘧啶的 3% ,而 90 %的 5 m C存在于 Cp G序列中。哺乳动物 DNA中 5 0 %～ 90 %的…     

DNA甲基转移酶1与妇科恶性肿瘤

DNA甲基转移酶1（DNMTl）作为DNA甲基转移酶（DNMT）家族的主要成员,对维持和调节肿瘤细胞全基因组和局部区域甲基化起着核心作用。DNMTl在妇科恶性肿瘤中高表达,引起基因DNA的甲基化异常,特别是抑癌基因的高甲基化,继而造成相关基因表达沉默,导致细胞的恶性生长。     

DNA甲基化与肿瘤

DNA的甲基化在本文中指甲基基团与基因组中 CpG二核苷酸的胞嘧啶环第 5碳原子以共价键的形式结合 , 形成 5- 甲基胞嘧啶 . 甲基化过程由 DNA甲基转移酶 (DNMT)催化 , 使用 S- 腺苷蛋氨酸作为甲基供体 . 甲基化虽然不改变核苷酸的序列 , 但和哺乳动物的基因表达调控密切相关 . 比如它能抑制转录 (详见后文 ), 并且在胚胎发育、 X- 染色体失活、基因印迹、抑制寄生 DNA序列的表达、 DNA损伤修复以及基因组稳定性等方面具有重要作用 .     

DNA甲基化与肿瘤的关系

DNA甲基化在基因组的稳定性和肿瘤发生中起着重要作用。肿瘤可发生许多基因的异常甲基化,尤其是抑癌基因的高甲基化对肿瘤发生有重要作用。由于DNA甲基化的可逆转特性,因此可以作为恶性肿瘤的治疗靶点。现对甲基化在肿瘤发生中的作用和临床意义作一综述。     

DNA甲基化与肿瘤的关系

DNA甲基化在基因组的稳定性和肿瘤发生中起着重要作用。肿瘤可发生许多基因的异常甲基化，尤其是抑癌基因的高甲基化对肿瘤发生有重要作用。由于DNA甲基化的可逆转特性，因此可以作为恶性肿瘤的治疗靶点。现对甲基化在肿瘤发生中的作用和临床意义作一综述。     

DNA甲基化基因DNMT1的研究进展

DNA甲基转移酶1(DNMT1)是哺乳动物基因组表观遗传修饰中DNA甲基化的关键基因,其编码的蛋白是一种分子量大且功能复杂的酶,具有多种调控功能,参与机体发育过程中干细胞生长、细胞增殖、器官发育、衰老和肿瘤发生等多个生物学过程。本文将对DNMT1基因的结构与分子作用机制进行介绍,并总结其表达调控、生物学功能及其与肿瘤等人类疾病相关的研究进展。     

m6A甲基化在妇科恶性肿瘤中的研究进展

近年来大量研究表明表观遗传现象m6A甲基化与恶性肿瘤的发生发展密切相关,其通过甲基转移酶、去甲基酶及m6A结合蛋白影响mRNA的剪切、翻译及稳定性从而调控肿瘤细胞的增殖、分化及耐药性。随着m6A甲基化在恶性肿瘤方面研究的不断深入,其在宫颈癌、子宫内膜癌和卵巢癌等妇科恶性肿瘤中的相关作用机制也逐渐被发现。本文将对近年来m6A甲基化在宫颈癌、子宫内膜癌和卵巢癌等发病率较高的妇科恶性肿瘤中的相关研究进展作一综述,介绍甲基转移酶、去甲基酶及m6A结合蛋白通过对mRNA的作用修饰而调控肿瘤发生发展的机制。其相关研究结果亦将为妇科恶性肿瘤的预防和治疗提供新的检测方法和作用靶点。     

DNA甲基转移酶在肿瘤形成中的研究进展

DNA甲基化是基因表达调控中重要的调节方式之一,可通过影响癌基因和抑癌基因的表达以及基因组的稳定性而参与肿瘤形成。DNA甲基化是由DNA甲基转移酶(DNMT)催化发生并维持的,并认为DNMT活性增高是肿瘤细胞具有特征的早期分子改变,因而受到越来越多的学者关注。     

Delta DNMT3B variants regulate DNA methylation in a promoter-specific manner

DNA methyltransferase 3B (DNMT3B) is critical in de novo DNA methylation during development and tumorigenesis. We recently reported the identification of a DNMT3B subfamily, DeltaDNMT3B, which contains at least seven variants, resulting from alternative pre-mRNA splicing. DeltaDNMT3Bs are the predominant expression forms of DNMT3B in human lung cancer. A strong correlation was observed between the promoter methylation of RASSF1A gene but not p16 gene (both frequently inactivated by promoter methylation in lung cancer) and expression of DeltaDNMT3B4 in primary lung cancer, suggesting a role of DeltaDNMT3B in regulating promoter-specific methylation of common tumor suppressor genes in tumorigenesis. In this report, we provide first experimental evidence showing a direct involvement of DeltaDNMT3B4 in regulating RASSF1A promoter methylation in human lung cancer cells. Knockdown of DeltaDNMT3B4 expression by small interfering RNA resulted in a rapid demethylation of RASSF1A promoter and reexpression of RASSF1A mRNA but had no effect on p16 promoter in the lung cancer cells. Conversely, normal bronchial epithelial cells with stably transfected DeltaDNMT3B4 gained an increased DNA methylation in RASSF1A promoter but not p16 promoter. We conclude that promoter DNA methylation can be differentially regulated and DeltaDNMT3Bs are involved in regulation of such promoter-specific de novo DNA methylation.     

The involvement of promoter methylation and DNA methyltransferase-1 in the regulation of EpCAM expression in oral squamous cell carcinoma

Epithelial cell adhesion molecule (EpCAM) is important for cell proliferation and differentiation but mechanisms regulating their expression are unclear. Because EpCAM may play a role in carcinogenesis, we investigated the clinicopathologic significance of its expression in oral squamous cell carcinoma (OSCC) and the involvement of DNA methylation machinery in regulation of EpCAM expression during tumorigenesis. Immunohistochemical staining for EpCAM expression and DNA methyltransferase-1 (DNMT1) was done in 112 OSCC cases. Tumor genomic DNA was extracted and EpCAM promoter methylation was examined by methylation-specific polymerase chain reaction in 72 OSCC specimens. Immunoreactivity and methylation were correlated with clinicopathologic features. EpCAM expression was undetectable in normal epithelium; high expression was observed in 51% (57/112) of OSCC. Heterogeneity and plasticity of EpCAM expression was observed during tumor development. Allele methylation was found in 51% (37/72) of OSCC cases analyzed. EpCAM expression was associated with promoter methylation (p = 0.008). However, EpCAM expression and promoter methylation did not correlate with clinicopathologic OSCC variables. DNMT1 expression was occasionally observed in basal cells of normal epithelium; high expression was observed in 47% (53/112) of OSCC. DNMT1 did not correlate with EpCAM expression or methylation status. High DNMT1 expression correlated with tumor size (p < 0.0001) histologic differentiation (p = 0.012) and clinical stage (p < 0.0001) of OSCC. EpCAM expression increased during development of OSCC. EpCAM promoter methylation is associated with EpCAM expression levels in OSCC, suggesting an epigenetically mediated regulation of EpCAM expression. Increased DNMT1 protein expression may be involved in histogenesis and progression of OSCC.     

m6A甲基化在多种消化道肿瘤中的研究进展

m6A甲基化是真核细胞mRNA中最常见的修饰方式,可在不改变碱基序列的基础上调控基因转录后的表达水平。m6A甲基化通过甲基转移酶和去甲基转移酶,在表观遗传修饰水平调控原癌基因、抑癌基因等的表达来影响肿瘤的发生发展。本文就m6A甲基化的相关概念、生物学功能以及在消化系统肿瘤中的最新研究进展作一综述,以期为消化道肿瘤的诊断、治疗、预后及监测提供新的有效策略。     

m6A甲基化在肿瘤中修饰非编码RNA的最新研究进展

非编码RNA（non-coding RNA,ncRNA）在细胞分化、血管生成、免疫应答、炎症反应以及肿瘤发生发展中具有重要作用。m6A（N6-methyladenosine）甲基化是真核生物中最常见的RNA修饰方式之一,主要见于信使RNA（messenger RNA,mRNA）。m6A甲基化修饰主要有三种酶参与完成,包括甲基转移酶、去甲基化酶和甲基化识别酶,并且在昼夜节律调控、基因表达、细胞分化、胚胎发育、应激反应及肿瘤发生中发挥作用。目前已有研究证实m6A甲基化通过调控ncRNAs在肿瘤生长、侵袭和转移中具有重要作用。本文将对m6A甲基化在肿瘤中修饰ncRNAs的最新研究进展进行综述。     

对顺铂耐药胃癌细胞的DNA甲基化表型标志物初筛

目的:寻找和鉴定对顺铂耐药胃癌细胞的异常甲基化基因。方法:我们拟胃癌细胞和耐药细胞为研究对象,采用DNA甲基化芯片,对比分析两种细胞DNA甲基化表达谱差异,结合甲基化特异性PCR（MS-PCR）技术验证获得的异常甲基化基因。结果:利用DNA甲基化谱芯片对胃癌细胞和耐药细胞两个细胞系的基因组DNA甲基化谱进行分析,发现1 095个甲基化差异位点;并筛选出36个高甲基化,14个低甲基化修饰基因。然后通过MS-PCR方法对这50个基因的甲基化修饰在细胞水平上又进行了验证分析,最终筛选出与甲基化谱芯片结果一致的 14种基因,包括11种高甲基化和3种低甲基化修饰基因。结论:胃癌癌细胞发生顺铂耐药时,细胞基因组存在广泛的DNA甲基化修饰改变。     

DNA methylation screening identifies driver epigenetic events of cancer cell survival

Cancer cells typically exhibit aberrant DNA methylation patterns that can drive malignant transformation. Whether cancer cells are dependent on these abnormal epigenetic modifications remains elusive. We used experimental and bioinformatic approaches to unveil genomic regions that require DNA methylation for survival of cancer cells. First, we surveyed the residual DNA methylation profiles in cancer cells with highly impaired DNA methyltransferases. Then, we clustered these profiles according to their DNA methylation status in primary normal and tumor tissues. Finally, we used gene expression meta-analysis to identify regions that are dependent on DNA methylation-mediated gene silencing. We further showed experimentally that these genes must be silenced by DNA methylation for cancer cell survival, suggesting these are key epigenetic events associated with tumorigenesis.     

How does DNA methylation mark the fate of cells?

Since every cell of a multicellular organism contains the same genome, it is intriguing to understand why genetically homogenous cells are different from each other and what controls this. Several observations indicate that DNA methylation has an essential regulatory function in mammalian development, which is to establish the correct pattern of gene expression, and that DNA methylation pattern is tightly correlated with chromatin structure. Various physiological processes are controlled by specific DNA methylation patterns including genomic imprinting, inactivation of the X chromosome, regulation of tissue-specific gene expression and repression of transposons. Moreover, aberrant methylation could confer a selective advantage to cells, leading to cancerous growth. In this review we focus on the epigenetic molecular mechanisms during normal development and discuss how DNA methylation could affect the expression of genes leading to cancer transformation.