骨髓增生异常综合征的治疗新策略——-表观基因调控

 表观遗传学是研究不涉及DNA序列变化的、可遗传的基因表达调控方式的一门学科。肿瘤中表观遗传学的改变包括影响基因差异表达的DNA甲基化、组蛋白乙酰化/组蛋白去乙酰化和染色质重塑等几个方面。在骨髓增生异常综合征（MDS）中也能观察到这种表观遗传学改变,这一领域在临床和实验中都有极大的研究价值。重点阐述了表观基因调控在MDS治疗中的进展,主要涉及DNA去甲基化和组蛋白去乙酰化酶抑制剂等药物。     

营养与肿瘤表观遗传学关系的研究进展——组蛋白修饰机制

表观遗传学是研究没有DNA序列变化,但可遗传的基因表达(活性)的改变.目前认为表观遗传的信息包括核小体构型的变化(ATP依赖的染色体重构);基因组印记;X染色体失活;DNA甲基化;染色体蛋白的改变,包括组蛋白的修饰如乙酰化、甲基化、磷酸化、多聚ADP-核糖基化、赖氨酸残基(Lys)的生物素(酰)化等,组蛋白变体的替换,非组蛋白的改变;非编码RNA调控转录.长期以来人们一直认为基因突变参与肿瘤的形成,近年来越来越多的证据表明,肿瘤的形成受遗传学修饰和表观遗传修饰的影响,表观遗传修饰在肿瘤进展中同样具有非常重要的作用.饮食是影响健康的重要因素,与肿瘤关系密切.本文对有关表观遗传学的组蛋白修饰机制的研究作一综述,并分别对目前其在肿瘤发生、发展的分子机制研究中所起作用及其在肿瘤预防和治疗的应用方面进行初步总结;概述了食物营养与肿瘤表观遗传学组蛋白修饰机制关系的近期研究情况.     

表观遗传修饰在白血病中的作用

 在过去几年里,人们对表观遗传疾病的机制有了新的认识。人类疾病与DNA甲基化、组蛋白乙酰化和甲基化、RNA相关性沉默的表观遗传修饰有关。表观遗传修饰与细胞生长、分化、凋亡、转化及肿瘤进展相关基因的转录密切相关。长期以来人们一直认为基因突变参与肿瘤的形成,近年来越来越多的证据表明,肿瘤的形成受遗传学修饰和表观遗传修饰的影响,表观遗传修饰在肿瘤的形成中也具有非常重要的作用。现阐述了DNA甲基化、组蛋白翻译后修饰异常及小分子干扰（siRNA）对白血病形成的影响,为白血病治疗提供新的前景。     

胃癌表观遗传学研究

生物基因组中表现遗传学信息决定着表观基因型,为蛋白质的制造提供何时、何地、以何种方式行使遗传信息的指令.长期的分子生物学研究揭示了一系列表观遗传学的改变与胃癌的发生、发展有关,这些改变涉及抑癌基因、细胞粘附分子、细胞周期调节因子和遗传不稳定性等,相关表观遗传学分子机制主要包括DNA甲基化、基因组印记异常表达、组蛋白异常乙酰化、microRNA改变等.利用MSP等方法检测胃癌患者血清中相关基因异常甲基化是一种具有较高灵敏度和特异性的方法,可以作为胃癌诊断的辅助手段.DNA甲基化抑制剂和组蛋白去乙酰化酶抑制剂联合使用,能够更有效地抑制肿瘤的生长,有可能成为治疗胃癌的新途径,具有一定临床应用价值.     

表观遗传学在白血病研究中的新进展

 近年来研究表明表观遗传学异常是白血病发病机制中的重要组成部分。许多白血病都伴随表观遗传学的异常变化。白血病的DNA去甲基化治疗和组蛋白去乙酰化抑制剂治疗是建立在表观修饰的基础上不同于传统化疗的新方法,目前已开始应用于几种白血病的治疗。现就DNA甲基化和组蛋白修饰在白血病的发生、发展、治疗和预后等方面的最新进展作简要介绍。     

表观遗传学在白血病研究中的新进展

近年来研究表明表观遗传学异常是白血病发病机制中的重要组成部分.许多白血病都伴随表观遗传学的异常变化.白血病的DNA去甲基化治疗和组蛋白去乙酰化抑制剂治疗是建立在表观修饰的基础上不同于传统化疗的新方法 ,目前已开始应用于几种白血病的治疗.现就DNA甲基化和组蛋白修饰在白血病的发生、发展、治疗和预后等方面的最新进展作简要介绍.     

表观遗传学在白血病研究中的新进展

近年来研究表明表观遗传学异常是白血病发病机制中的重要组成部分.许多白血病都伴随表观遗传学的异常变化.白血病的DNA去甲基化治疗和组蛋白去乙酰化抑制剂治疗是建立在表观修饰的基础上不同于传统化疗的新方法 ,目前已开始应用于几种白血病的治疗.现就DNA甲基化和组蛋白修饰在白血病的发生、发展、治疗和预后等方面的最新进展作简要介绍.     

表观遗传学在白血病研究中的新进展

近年来研究表明表观遗传学异常是白血病发病机制中的重要组成部分.许多白血病都伴随表观遗传学的异常变化.白血病的DNA去甲基化治疗和组蛋白去乙酰化抑制剂治疗是建立在表观修饰的基础上不同于传统化疗的新方法 ,目前已开始应用于几种白血病的治疗.现就DNA甲基化和组蛋白修饰在白血病的发生、发展、治疗和预后等方面的最新进展作简要介绍.     

表观遗传学在白血病研究中的新进展

近年来研究表明表观遗传学异常是白血病发病机制中的重要组成部分.许多白血病都伴随表观遗传学的异常变化.白血病的DNA去甲基化治疗和组蛋白去乙酰化抑制剂治疗是建立在表观修饰的基础上不同于传统化疗的新方法 ,目前已开始应用于几种白血病的治疗.现就DNA甲基化和组蛋白修饰在白血病的发生、发展、治疗和预后等方面的最新进展作简要介绍.     

表观遗传学在白血病研究中的新进展

近年来研究表明表观遗传学异常是白血病发病机制中的重要组成部分.许多白血病都伴随表观遗传学的异常变化.白血病的DNA去甲基化治疗和组蛋白去乙酰化抑制剂治疗是建立在表观修饰的基础上不同于传统化疗的新方法 ,目前已开始应用于几种白血病的治疗.现就DNA甲基化和组蛋白修饰在白血病的发生、发展、治疗和预后等方面的最新进展作简要介绍.     

大肠癌表观遗传修饰在东西方人口中的异同研究

大肠癌对全世界人口的危害仍尤为重大,在其研究领域,大肠癌表观遗传学的研究越来越受到研究者重视。从大肠癌表观遗传学中的DNA甲基化和组蛋白修饰两个主要方面,对比分析了东西方人口中大肠癌患者之间存在的异同。接着,初步介绍了东西方大肠癌患者用作生物标识和治疗靶点的表观遗传修饰基因的异同点。分析表明,虽然大肠癌在世界范围内有一些共同的特征,但其在不同人种中确实存在某些明显的表观遗传的不同,例如特异性基因甲基化以及组蛋白修饰位点和甲基化,乙酰化的程度不同在各国的研究中都已得到证实,这就为不同人种中大肠癌特异性的诊断、治疗及预后提供了依据。在进一步的规范研究方法和增加样本量的情况下,相信更多的大肠癌组织特异性的分子靶点将会被发现,继而针对单个患者的个体化治疗将有望实现。     

Epigenetic inactivation of DNA repair in breast cancer

The study of epigenetic mechanisms in cancer, such as DNA methylation and histone modifications, has revealed a plethora of events that contribute to cancer through stable changes in the expression of genes critical to transformation pathways. In this mini review we look at the different epigenetic modifications prevalent in this neoplastic phenotype, focusing on breast cancer. Most encouragingly, research in epigenetics has led to improved survival of patients with certain forms of lymphoma and leukemia through the use of drugs that alter DNA methylation and histone acetylation. Thus, we look at the clinical utility of targeting epigenetic pathways. In addition, we explore numerous other clinical applications of epigenetics, in areas such as cancer screening and early detection, prevention, classification for epidemiology and prognostic purposes, and predicting outcomes after standard therapy.     

Epigenetic changes in prostate cancer: implication for diagnosis and treatment

Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death among men in the United States. DNA methylation and histone modifications are important epigenetic mechanisms of gene regulation and play essential roles both independently and cooperatively in tumor initiation and progression. Aberrant epigenetic events such as DNA hypo- and hypermethylation and altered histone acetylation have both been observed in prostate cancer, in which they affect a large number of genes. Although the list of aberrantly epigenetically regulated genes continues to grow, only a few genes have, so far, given promising results as potential tumor biomarkers for early diagnosis and risk assessment of prostate cancer. Thus, large-scale screening of aberrant epigenetic events such as DNA hypermethylation is needed to identify prostate cancer-specific epigenetic fingerprints. The reversibility of epigenetic aberrations has made them attractive targets for cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases, leading to reactivation of silenced genes. More studies into the mechanism and consequence of demethylation are required before the cancer epigenome can be safely manipulated with therapeutics as a treatment modality. In this review, we examine the current literature on epigenetic changes in prostate cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease.     

组蛋白乙酰化修饰在基因表达调控中的作用机制

表观遗传学是指 DNA序列变化以外的可遗传的基因表达改变,这种影响基因转录活性而不涉及DNA序列改变的基因表达调控方式称为表观转录调控,组蛋白乙酰化修饰是基因表观转录调控的重要机制.组蛋白翻译后修饰所引起的染色质结构重塑在真核生物基因表达调控中发挥着重要的作用.组蛋白乙酰化主要由组蛋白乙酰化酶 （histone acetylases, HATs） 和组蛋白去乙酰化酶（ Histone deacetylases, HDACs） 催化完成,HATs 通过在组蛋白赖氨酸残基乙酰化,激活基因转录,而HDACs 使组蛋白去乙酰化,抑制基因转录.组蛋白乙酰化和去乙酰化与基因的表达调控密切相关,HATs和HDACs之间的动态平衡控制着染色质的结构和基因的表达,组蛋白乙酰化状态的失衡与肿瘤发生密切相关.最近有研究发现,肿瘤细胞的组蛋白大部分呈低乙酰化状态.组蛋白乙酰化修饰对基因表达调控及其在肿瘤发生发展中的作用具有重要意义.因此,基于细胞内组蛋白乙酰化调控机制设计开发抗肿瘤药物成为研究热点.组蛋白去乙酰化酶抑制剂可以增强细胞内组蛋白乙酰化状态,从而改变肿瘤的生物学特性,而且去乙酰化酶抑制剂作用靶点是整个基因组而不是单个基因,所以去乙酰化酶抑制剂在肿瘤治疗中具有较好的应用前景.     

Demethylation by 5-aza-2'-deoxycytidine in colorectal cancer cells targets genomic DNA whilst promoter CpG island methylation persists

Background  

DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. Aberrant epigenetic gene silencing in tumours is a frequent event, yet the factors which dictate which genes are targeted for inactivation are unknown. DNA methylation and histone acetylation can be modified with the chemical agents 5-aza-2'-deoxycytidine (5-aza-dC) and Trichostatin A (TSA) respectively. The aim of this study was to analyse de-methylation and re-methylation and its affect on gene expression in colorectal cancer cell lines treated with 5-aza-dC alone and in combination with TSA. We also sought to identify methylation patterns associated with long term reactivation of previously silenced genes.     

Epigenetics in bladder cancer

Bladder cancer (BC) is the second most common malignancy of the genitourinary tract and the second leading cause of cancer death in patients with urinary tract malignancies. DNA methylation and histone modifications are important epigenetic mechanisms of gene regulation and play essential roles both independently and cooperatively in tumor initiation and progression. Aberrant epigenetic events such as DNA hypermethylation and altered histone acetylation have both been observed in bladder cancer, in which they affect a large number of genes. Although the list of aberrantly epigenetically regulated genes continues to grow, combination analysis including several candidate genes has given promising results of potential tumor biomarkers for the early diagnosis and risk assessment of bladder cancer. Thus, large-scale screening of aberrant epigenetic events such as DNA hypermethylation is needed to identify bladder cancer-specific epigenetic fingerprints. The reversibility of epigenetic aberrations has made them attractive targets for cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases, leading to the reactivation of silenced genes. In this review, we examine the current literature on epigenetic changes in bladder cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease.     

Epigenetic silencing of the candidate tumor suppressor gene Per1 in non-small cell lung cancer.

PURPOSE: Epigenetic events are a critical factor contributing to cancer development. The purpose of this study was to identify tumor suppressor genes silenced by DNA methylation and histone deacetylation in non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: We used microarray analysis to screen for tumor suppressor genes. RESULTS: We identified Per1, a core circadian gene, as a candidate tumor suppressor in lung cancer. Although Per1 levels were high in normal lung, its expression was low in a large panel of NSCLC patient samples and cell lines. Forced expression of Per1 in NSCLC cell lines led to significant growth reduction and loss of clonogenic survival. Recent studies showed that epigenetic regulation, particularly histone H3 acetylation, is essential for circadian function. Using bisulfite sequencing and chromatin immunoprecipitation, we found that DNA hypermethylation and histone H3 acetylation are potential mechanisms for silencing Per1 expression NSCLC. CONCLUSIONS: These results support the hypothesis that disruption of circadian rhythms plays an important role in lung tumorigenesis. Moreover, our findings suggest a novel link between circadian epigenetic regulation and cancer development.