DNA甲基化转移酶及DNA甲基化转移酶抑制剂在肿瘤研究中的新视角

表观遗传改变例如DNA甲基化涉及多种癌症的发生和进展。DNA甲基化包括可逆的甲基基团添加至CpG二核苷酸中5′位胞嘧啶上。而DNA甲基化转移酶(DNA methyltransferases,DNMT)是负责甲基基团添加至CpG二核苷酸的酶,与组蛋白修饰一起,是发生于转录抑制所必须的起始事件。已经证明在多种人恶性肿瘤中DNMT的表达增高,并且通过DNMT介导的基因失活促进肿瘤进展。DNMT在衰老与凋亡过程中都起到一定作用。表观遗传改变是潜在可逆的,这刺激DNA甲基化抑制剂药理学的发展,为肿瘤的治疗提供了一个新的途径。     

胆囊癌DNA甲基化修饰与治疗研究进展

胆囊癌是一种罕见但恶性程度极高的肿瘤,早期诊断困难,预后差,多药耐药,发病机制尚不明确。关于胆囊癌的研究主要集中在早期诊断生物标志物和治疗靶点的寻找。胆囊癌被认为是一种表观遗传异常肿瘤,DNA甲基化是其中最常见的一种修饰异常,且随肿瘤进展不断增加,DNA甲基化促进胆囊癌演变及发展,可作为其潜在生物标志物。此外,由于DNA甲基化的可逆性,DNA甲基化抑制剂有望通过与其他药物的联合应用,改善患者预后及耐药性。本研究我们将从DNA甲基化对胆囊癌的调控进行讨论,希望能为胆囊癌的早期诊断、预防和治疗提供一些研究思路。     

淋巴瘤的表观遗传学及其临床意义

在肿瘤形成过程中包含两大类机制，即遗传学机制和表观遗传学机制。肿瘤的表观遗传学主要体现在DNA甲基化模式上，一些肿瘤抑制基因的启动子的高甲基化及整个基因组的低甲基化状态。对肿瘤表观遗传学深入研究将对淋巴瘤的发生发展机制和临床诊断治疗起到重要作用。     

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。     

淋巴瘤的表观遗传学及其临床意义

在肿瘤形成过程中包含两大类机制,即遗传学机制和表观遗传学机制。肿瘤的表观遗传学主要体现在DNA甲基化模式上,一些肿瘤抑制基因的启动子的高甲基化及整个基因组的低甲基化状态。对肿瘤表观遗传学深入研究将对淋巴瘤的发生发展机制和临床诊断治疗起到重要作用。     

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。     

地西他滨在恶性血液肿瘤治疗中的应用

 地西他滨（DAC）是一种甲基化抑制剂,其不同于传统的化疗药物,具有独特的作用机制,并代表了新的治疗观念。甲基化存在于几乎所有的细胞内,通过抑制DNA甲基转移酶,引起DNA低甲基化和细胞分化或凋亡来发挥抗肿瘤作用。现就甲基化抑制剂DAC在恶性血液肿瘤治疗方面的应用进行综述。     

肺癌表观遗传学治疗的研究进展

肺癌是目前发病率和死亡率较高的恶性肿瘤之一, 其5年生存率不到15%。研究表明肺癌的发生是多种因素造成的, 表观遗传是重要因素之一。近年来, 随着甲基化转移酶抑制剂及组蛋白去乙酰化酶抑制剂等表观治疗药物在临床的成功应用, 以及它们具有增加肿瘤化疗敏感程度的作用, 表观遗传成为近来研究的热点。本文就表观遗传学中DNA甲基化、乙酰化及肿瘤化疗敏感性在肺癌诊断及治疗等方面的研究进展作综述。      

骨髓增生异常综合征表观遗传学治疗进展

 表观遗传改变与基因改变有一个重要的区别就是表观遗传改变是可逆的,通过使用相应的表观遗传药物可使沉默的抑癌基因重新表达。骨髓增生异常综合征（MDS）的表观遗传治疗已经取得了很大的发展,当前应用于临床的表观遗传药物主要包括DNA去甲基化药物和去乙酰化酶抑制剂。得到FDA批准上市的DNA去甲基化药物5-氮杂胞苷和地西他滨均为MDS治疗药物,可作为中高危患者尤其是不能耐受化疗的老年患者重要的治疗选择;去乙酰化酶抑制剂如丙戊酸等目前在治疗MDS中大多处于I期临床试验阶段,可能在治疗低危MDS中有一定价值,但其剂量和治疗效果尚需进一步评估;去甲基化药物和去乙酰化抑制剂二者联用治疗MDS可能具有协同作用,但目前的临床试验尚不能证实其优于去甲基化药物的单用,仍需大样本的临床病例和合理的治疗方案来验证其安全有效性。     

DNA甲基转移酶在肿瘤发病机制中的研究进展北大核心CSCD

0引言 与经典的遗传学不同,表观遗传学是指在DNA序列未发生异常改变的前提下,基因的功能发生了叮遗传的信息变化,并最终导致了表型的改变。DNA甲基化是表观遗传学修饰的主要形式之一,而DNA甲基转移酶（DNA methyltransferase,DNMT）则是DNA甲基化的主要调节酶。本文就DNMT在肿瘤中的研究进展作一综述。     

DNA methylation and cancer therapy: new developments and expectations

PURPOSE OF REVIEW: In addition to having genetic causes, cancer can also be considered an epigenetic disease. The main epigenetic modification is DNA methylation, and patterns of aberrant DNA methylation are now recognized to be a common hallmark of human tumors. One of the most characteristic features is the inactivation of tumor-suppressor genes by CpG-island hypermethylation of the CpG islands located in their promoter regions. These sites, among others, are the targets of DNA-demethylating agents, the promising chemotherapeutic drugs that are the focus of this article. RECENT FINDINGS: Four exciting aspects have recently arisen at the forefront of the advancements in this field: first, the development of new compounds with DNA-demethylating capacity that are less toxic (for example, procaine) and may be administered orally (for example, zebularine); second, a better knowledge of the molecular mechanisms underlying the action of these drugs for particular genes and throughout the genome; third, the establishment of more reliable techniques to measure the effects of these drugs in clinical samples, such as high-performance capillary electrophoresis; and fourth, a decisive effort in the clinical trials that has merited the approval of 5-azacytidine by the U.S. Food and Drug Administration for the treatment of myelodysplastic syndrome. SUMMARY: We are at the dawn of an era when epigenetic drugs will be an important weapon in our arsenal in the war against cancer. Hematological malignancies have provided a promising starting point, but studies will surely extend to all solid tumors. However, we need to continue our research to develop more specific DNA-demethylating agents, to understand their biologic effects, and to determine whether they may be successfully combined with other epigenetic drugs, such as the inhibitors of histone deacetylases, and classic chemotherapy compounds.     

CDK12基因在恶性肿瘤中的研究进展

CDK12属于转录相关的细胞周期蛋白依赖性激酶（cyclin-dependent kinases,CDKs）,在转录调控、mRNA剪接、DNA损伤修复、细胞生长和分化、调控表观遗传修饰、维持基因组稳定等多种细胞进程中发挥重要作用。目前已在多种实体瘤中检测到CDK12基因的体细胞变异,如前列腺癌、卵巢癌、乳腺癌、黑色素瘤、食管癌、子宫内膜癌、膀胱癌、结直肠癌和头颈鳞状细胞癌等。近期研究表明CDK12发生突变或缺失会引起恶性肿瘤患者对PARP抑制剂、铂类化疗药物以及免疫治疗敏感,因此有望成为肿瘤治疗的新靶点。     

弥漫大B细胞淋巴瘤的DNA甲基化改变及治疗进展

弥漫大B细胞淋巴瘤(DLBCL)异质性较高,具有不同的临床和病理特征,是成人淋巴瘤的一种常见类型。尽管一部分DLBCL已经可以治愈,但难治和复发患者的治疗仍然具有挑战性。近年来,DNA甲基化等表观遗传修饰成为DLBCL的研究热点。调控甲基化修饰的基因突变及抑癌基因甲基化修饰在DLBCL发病及预后中起到关键作用。本文对DLBCL的DNA甲基化研究进展进行综述。     

组蛋白甲基化修饰在多发性骨髓瘤发生发展中的作用研究进展

多发性骨髓瘤（multiple myeloma,MM）是一类骨髓浆细胞恶性克隆性疾病。尽管MM的治疗有所进展,但大部分患者均会复发或耐药,因此亟需新的治疗靶点。除了遗传缺陷和骨髓微环境紊乱外,越来越多的证据表明表观遗传学调控异常在MM发病中发挥重要作用。表观遗传因子的突变往往与基因组不稳定、耐药性和疾病进展有关,且这些突变在治疗后有所增加,尤其是组蛋白甲基化和DNA甲基化修饰酶。本文就组蛋白甲基化修饰在MM中的作用进行综述,重点讨论组蛋白甲基化转移酶（his?tone methyltransferases,HMTs）和组蛋白去甲基化酶（histone demethylases,HDMs）在MM发生发展中的作用。      

淋巴瘤表观遗传学靶向治疗的进展

淋巴瘤是一类起源于淋巴结和淋巴组织的异质性肿瘤。表观遗传学为研究不改变DNA序列，基因表达改变可遗传的一门新兴学科。淋巴瘤的发病、进展与表观遗传异常密切相关。针对表观遗传异常的靶向药物，主要包括DNA甲基转移酶抑制剂（DNA methyltransferase inhibitors，DNMTis）、组蛋白去乙酰化酶抑制剂、EZH2抑制剂、PRMT抑制剂及BET抑制剂等，在淋巴瘤的靶向治疗中凸显出绝对优势。本文分析近年来表观遗传药物在淋巴瘤中的治疗进展，旨在为淋巴瘤的靶向治疗提供新思路。      

DNA甲基化在肺癌中的研究进展

肺癌是严重威胁人类生命健康的恶性肿瘤之一。DNA甲基化作为表观遗传学的主要组成部分,其在细胞增殖、凋亡、DNA修复、肿瘤侵袭和转移等生物过程中起着重要作用。大量研究证明,DNA甲基化在肺癌的发展中扮演着重要的角色,本文就近年来DNA甲基化在肺癌中的发病机制、诊断、治疗及预后的研究进展作一综述。     

Epigenetics in cancer: what's the future?

Epigenetics is a rapidly expanding field that focuses on stable changes in gene expression that are not accompanied by changes in DNA sequence and that are mediated primarily by DNA methylation and histone modifications. Disruption of the epigenome is a fundamental mechanism in cancer, and several epigenetic drugs that have proved to prolong survival and to be less toxic than conventional chemotherapy were recently approved by the FDA for cancer treatment. These include azacitidine (Vidaza), decitabine (Dacogen), vorinostat (Zolinza), and romidepsin (Istodax). Promising results of combination clinical trials with DNA methylation inhibitors and histone deacetylase inhibitors have recently been reported, and data are emerging that describe molecular determinants of clinical responses. Despite significant advances, challenges remain, including a lack of predictive markers, unclear mechanisms of response and resistance, and rare responses in solid tumors. Preclinical studies are ongoing with novel classes of agents that target various components of the epigenetic machinery. In this review, we focus on recent clinical and translational data in the epigenetics field that have potential in cancer therapy.     

Epigenetische Inaktivierung von Genexpression

In addition to the multiple genetic aberrations described in hematologic neoplasias and solid tumors, epigenetic lesions in these malignancies also offer novel therapeutic targets since they are potentially reversible. Up to now, gene silencing of tumor suppressors, proteins involved in cell adhesion, metastasis and proapoptotic activity have been identified in virtually every type of human malignancy. Two major alterations have been described which can be antagonized by drugs already approved by the FDA (two azanucleosides for the treatment of myelodysplastic syndrome, the inhibitor of histone deacetylases Zolinza®/Vorinostat®/SAHA for cutaneous T-cell lymphoma). Translational studies demonstrating the in vivo inhibition of DNA methylation, and subsequent re-expression of tumor suppressor proteins such as p15/INK4b have provided proof-of-principle that demethylating agents reactivate these genes in vivo. Similarly, histone deacetylation in vivo by treatment with phenylbutyrate, valproic acid, depsipeptide and other HDAC inhibitors demonstrates the efficacy of these drugs in remodeling chromatin structure. However, ongoing studies are addressing which of the (probably multiple) targets for epigenetic therapy are reactivated in vivo in different malignancies (e.g. by methylation profiling). Combination studies to attack the “silencer” phenotype of malignant cells on different levels of epigenetic control are ongoing. Most of these clinical developments were performed with low doses of azanucleosides in hematologic malignancies, and studies to extend these prolonged, low-dose schedules to different solid tumor entities will be of great interest.