共查询到19条相似文献,搜索用时 78 毫秒
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目的 对Zeste增强子同源物2(EZH2)在脑胶质瘤中的最新研究进展进行汇总,介绍在脑胶质瘤中EZH2与非编码RNA相互作用机制及功能,为开发以EZH2为靶点的脑胶质瘤新型治疗方法提供参考。方法 应用PubMed及CNKI期刊全文数据库检索系统,以“EZH2,脑胶质瘤,非编码RNA,表观遗传修饰”为中文关键词,以“EZH2,glioma, non-coding RNA,epigenetic modification”为英文关键词,检索2000-2022年发表的相关中英文文献。纳入标准:(1)EZH2在脑胶质瘤发生发展中的作用;(2)EZH2与非编码RNA调控脑胶质瘤的最新进展。排除标准:陈旧及重复的文献、研究结果不明确及不真实可靠的文献。最终共纳入符合条件文献87篇。结果 EZH2可以促进脑胶质瘤细胞的生长、侵袭和转移、代谢等。EZH2可作为非编码RNA如miRNA和lncRNA的上游基因来抑制miRNA和lncRNA表达,从而促进脑胶质瘤的发生发展。此外,EZH2还受到miRNA、lncRNA和circRNA的调控,即EZH2也可作为非编码RNA的下游靶基因来调控脑胶质瘤的恶性进展... 相似文献
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弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)是最常见的非霍奇金淋巴瘤(non-hodgkin lymphoma),并且是一组在临床表现、组织形态和预后等多方面具有很大异质性的恶性肿瘤,其发病机制错综复杂。近年来表观遗传学修饰在DLBCL的发生、发展中的重要作用是研究的热点。本文综述了近年来组蛋白甲基转移酶EZH2和MLL2在弥漫大B细胞淋巴瘤中的最新研究进展,为从表观遗传学的角度认识和治疗弥漫大B细胞淋巴瘤提供新认识。 相似文献
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目的 探讨EZH2过表达在MCF-7/ADR获得性耐药中的作用。方法 应用荧光定量PCR技术和Western blot技术分别检测EZH2在MCF-7和MCF-7/ADR中的mRNA和蛋白的相对表达量。将带有报告基因eGFP的EZH2 shRNA、EZH2 shRNA-scramble质粒分别转染MCF-7/ADR细胞后,用G418筛选获得稳转细胞株,应用荧光定量PCR技术验证EZH2 shRNA组EZH2 mRNA表达是否被抑制。采用WST-1方法检测EZH2 shRNA、EZH2 shRNA-scramble和阴性对照组细胞对阿霉素敏感性的变化情况。结果 MCF-7/ADR中EZH2 mRNA相对表达量约为MCF-7的2.52±1.523倍,MCF-7/ADR中EZH2蛋白相对表达量约为MCF-7的1.58±0.58倍,差异均有统计学意义(P<0.05)。EZH2 shRNA组稳转的细胞株EZH2 mRNA的抑制率约为84%(P<0.05),加入阿霉素后细胞增殖能力约下降25%(P<0.05),而EZH2 shRNA-scramble组和阴性对照组加入阿霉素后细胞增殖能力无明显变化。结论 在MCF-7/ADR细胞中EZH2 mRNA和蛋白的相对表达量较MCF-7细胞高。沉默EZH2的表达有可能逆转MCF-7/ADR细胞对阿霉素的耐药性。 相似文献
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目的:探讨EZH 2 基因对卵巢癌细胞增殖和转移能力的影响,及其在卵巢癌组织中的表达与临床病理学意义。方法:运用EZH 2 小干扰RNA(siRNA )转染卵巢癌OVCAR- 3 细胞株,Western blot方法分析OVCAR- 3 细胞中EZH 2 的蛋白表达;MTT 实验检测细胞增殖水平,Transwell 小室实验检测细胞侵袭和转移能力。另外,应用RT-PCR 和免疫组织化学法分别检测EZH 2 在卵巢癌组织中的mRNA 和蛋白表达情况。结果:与阴性对照组相比,EZH 2 siRNA 能明显降低OVCAR- 3 细胞的EZH 2 蛋白表达,并显著抑制肿瘤细胞的增殖能力(P=0.032);转染EZH 2 siRNA 的OVCAR- 3 穿膜细胞数,在侵袭实验中,siEZH 2 组为29.3 ± 5,与对照组(51± 6.8)比较,差异有统计学意义(P=0.027);在迁移实验中,siEZH 2 组的迁移细胞数为51.6 ± 7.7,显著低于对照组(72.3 ± 11.7,P=0.036)。 RT-PCR 检测发现,卵巢癌组织中的EZH 2 mRNA 表达水平明显高于正常组织。在免疫组化实验中,61.0%的卵巢癌组织呈EZH 2 蛋白高表达,而且与卵巢癌的T 分期、N 分期以及FIGO分期显著正相关(P<0.05)。 另外,单变量生存分析发现EZH 2 高表达与卵巢癌患者短生存期密切相关(P=0.007);多变量分析显示EZH 2 是卵巢癌的独立预后参数(P=0.047)。 结论:EZH 2 在卵巢癌的发生与进展中发挥着重要的作用,而且EZH 2 高表达是卵巢癌患者预后不良的独立分子指标。 相似文献
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EZH2在肝细胞性肝癌中的表达及其对HepG2增殖作用的研究 总被引:2,自引:0,他引:2
目的探讨EZH 2在肝细胞性肝癌中的表达及其对肝癌细胞株H epG 2增殖活性的影响。方法采用W estern-b lot和RT-PCR方法分析EZH 2与28例肝细胞性肝癌临床病理因素的关系;构建EZH 2 RNA i表达载体,观察其对H epG 2增殖活性的影响。结果在28例肝细胞性肝癌标本中,EZH 2在转录与蛋白水平,癌与癌旁之间差异均有显著性(mRNA 1.17±0.50 vs 0.50±0.14,P<0.01;P rote in 1.35±0.65 vs 0.38±0.20,P<0.01);EZH 2与临床病理特征分析中,EZH 2在肿瘤直径>5 cm组的表达显著高于直径≤5 cm组(1.71±0.68 vs 0.93±0.25,P<0.001),而EZH 2的表达与门静脉栓塞有无之间、肿瘤分化高、中、低之间则差异无显著性。成功构建EZH 2 RNA i表达载体pS ilencer 2.1-U 6(+),pS ilencer 2.1-U 6(+)转染显著阻滞了H epG 2细胞的增殖,并诱导H epG 2阻滞于G2/M期。结论EZH 2在肝细胞性肝癌表达上调,提示EZH 2在肝细胞性肝癌的发展中起重要作用。 相似文献
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DNA甲基化与肿瘤发生发展机制研究进展 总被引:2,自引:0,他引:2
表观遗传学在肿瘤发生发展中具有重要的作用,其中DNA甲基化被认为是肿瘤形成的重要机制之一。在肿瘤形成过程中,DNA甲基化的模式发生了巨大变化,包括整个基因组的去甲基化和部分区域高度甲基化两种现象。抑癌基因通常因高度甲基化而失活,这种基因沉默调控与体细胞突变共同促进了肿瘤的发展。目前对基因表达调控的研究加深了对基因沉默机制的理解,也为肿瘤发生机制研究及其早期诊断和潜在的治疗开辟新的方向。 相似文献
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目的:研究膀胱癌组织EZH2 和PTEN基因的表达,探讨其与膀胱癌临床病理特征及无瘤生存的关系。方法:制作80例膀胱移行细胞癌和10例正常膀胱黏膜(对照组)组织芯片,应用免疫组织化学方法检测EZH 2 和PTEN蛋白的表达,采用Kaplan-Meier 单因素和Cox 比例风险模型多因素分析其与膀胱癌无瘤生存的关系。结果:膀胱癌组织中EZH 2 和PTEN阳性表达率分别为80.0% 和45.0% 。EZH 2 和PTEN的阳性表达率在膀胱癌不同临床分期及病理分级组间存在显著性差异(P<0.05),且两者的表达呈负相关(P=0.033)。 全组膀胱癌患者术后平均无瘤生存期为39.4 个月,1、3、5 年无瘤生存率分别为70.0% 、55.2% 、41.4% 。单因素分析表明:病理分级、肿瘤数目和EZH 2 表达为影响膀胱癌预后的相关因素;多因素分析表明:病理分级、肿瘤数目和EZH 2 表达是膀胱癌复发的独立危险因素。结论:EZH 2 和PTEN异常表达与膀胱癌的发生、发展关系密切。病理分级、肿瘤数目和EZH 2 是膀胱癌预后的独立危险因素。 相似文献
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Theresa Baker Sujata Nerle Justin Pritchard Boyang Zhao Victor M. Rivera Andrew Garner Francois Gonzalvez 《Oncotarget》2015,6(32):32646-32655
Although targeted therapies have revolutionized cancer treatment, overcoming acquired resistance remains a major clinical challenge. EZH2 inhibitors (EZH2i), EPZ-6438 and GSK126, are currently in the early stages of clinical evaluation and the first encouraging signs of efficacy have recently emerged in the clinic. To anticipate mechanisms of resistance to EZH2i, we used a forward genetic platform combining a mutagenesis screen with next generation sequencing technology and identified a hotspot of secondary mutations in the EZH2 D1 domain (Y111 and I109). Y111D mutation within the WT or A677G EZH2 allele conferred robust resistance to both EPZ-6438 and GSK126, but it only drove a partial resistance within the Y641F allele. EZH2 mutants required histone methyltransferase (HMT) catalytic activity and the polycomb repressive complex 2 (PRC2) components, SUZ12 and EED, to drive drug resistance. Furthermore, D1 domain mutations not only blocked the ability of EZH2i to bind to WT and A677G mutant, but also abrogated drug binding to the Y641F mutant. These data provide the first cellular validation of the mechanistic model underpinning the oncogenic function of WT and mutant EZH2. Importantly, our findings suggest that acquired-resistance to EZH2i may arise in WT and mutant EZH2 patients through a single mutation that remains targetable by second generation EZH2i. 相似文献
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Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor 下载免费PDF全文
Daisuke Honma Osamu Kanno Jun Watanabe Junzo Kinoshita Makoto Hirasawa Emi Nosaka Machiko Shiroishi Takeshi Takizawa Isao Yasumatsu Takao Horiuchi Akira Nakao Keisuke Suzuki Tomonori Yamasaki Katsuyoshi Nakajima Miho Hayakawa Takanori Yamazaki Ajay Singh Yadav Nobuaki Adachi 《Cancer science》2017,108(10):2069-2078
Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non‐Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B‐cell lymphoma cells harboring gain‐of‐function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL‐AF9, MLL‐AF4, and AML1‐ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications. 相似文献
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Danielle P. Johnson Gabriella S. Spitz Shweta Tharkar Steven N. Quayle Jeffrey R. Shearstone Simon Jones Maria E. McDowell Hannah Wellman Jessica K. Tyler Bradley R. Cairns Mahesh B. Chandrasekharan Srividya Bhaskara 《Oncotarget》2015,6(7):4863-4887
Gain-of-function mutations in the catalytic site of EZH2 (Enhancer of Zeste Homologue 2), is observed in about 22% of diffuse large B-cell lymphoma (DLBCL) cases. Here we show that selective inhibition of histone deacetylase 1,2 (HDAC1,2) activity using a small molecule inhibitor causes cytotoxic or cytostatic effects in EZH2 gain-of-function mutant (EZH2GOF) DLBCL cells. Our results show that blocking the activity of HDAC1,2 increases global H3K27ac without causing a concomitant global decrease in H3K27me3 levels. Our data shows that inhibition of HDAC1,2 is sufficient to decrease H3K27me3 present at DSBs, decrease DSB repair and activate the DNA damage response in these cells. In addition to increased H3K27me3, we found that the EZH2GOF DLBCL cells overexpress another chemotherapy resistance factor − B-lymphoma and BAL-associated protein (BBAP). BBAP monoubiquitinates histone H4K91, a residue that is also subjected to acetylation. Our results show that selective inhibition of HDAC1,2 increases H4K91ac, decreases BBAP-mediated H4K91 monoubiquitination, impairs BBAP-dependent DSB repair and sensitizes the refractory EZH2GOF DLBCL cells to treatment with doxorubicin, a chemotherapy agent. Hence, selective HDAC1,2 inhibition provides a novel DNA repair mechanism-based therapeutic approach as it can overcome both EZH2- and BBAP-mediated DSB repair in the EZH2GOF DLBCL cells. 相似文献
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目的:探讨DNA 甲基转移酶(DNAmethyltransferase,DNMT 1)与EZH 2 在急性髓系白血病(acutemyeloidleukemia,AML )中的表达及其相关性。方法:采用荧光定量PCR(fluorescencequantitativePCR ,FQ-PCR)检测大连医科大学附属第二医院2014年1月至2015年1 月50例初治AML 患者骨髓细胞中DNMT 1 与EZH 2 mRNA 的表达水平,分析DNMT 1 表达水平与临床特征和预后的关系以及与EZH 2 的相关性。结果:50例AML 患者骨髓细胞中DNMT 1 mRNA 的表达显著高于30例正常供者(2.72± 0.73vs . 0.89±0.27,P < 0.01);EZH 2 的表达水平也显著高于正常供者(4.39± 1.06vs . 1.87± 0.33,P < 0.01);EZH 2 与DNMT 1 的表达水平呈显著正相关(r = 0.51,P = 0.002);DNMT 1 表达水平与外周血幼稚细胞比例≥ 60%(P < 0.05)、WBC≥ 50× 109/L (P < 0.05)呈显著相关;DNMT 1 高表达组患者中位生存时间15个月(95%CI 为9~19个月),显著低于DNMT 1 低表达组患者的32个月(95%CI 为27~40个月,P =0.006)。结论:DNMT 1 和EZH 2 在AML 患者中均高表达,两者表达水平呈正相关,DNMT 1 与AML 患者预后不良相关。 相似文献
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Bryson W Katona Yuanyuan Liu Anqi Ma Jian Jin Xianxin Hua 《Cancer biology & therapy》2014,15(12):1677-1687
Metastatic colon cancer has a 5-year survival of less than 10% despite the use of aggressive chemotherapeutic regimens. As signaling from epidermal growth factor receptor (EGFR) is often enhanced and epigenetic regulation is often altered in colon cancer, it is desirable to enhance the efficacy of EGFR-directed therapy by co-targeting an epigenetic pathway. We showed that the histone methyltransferase EZH2, which catalyzes methylation of histone H3 lysine 27 (H3K27), was upregulated in colon cancers in The Cancer Genome Atlas (TCGA) database. Since co-inhibition of both EGFR and EZH2 has not been studied in colon cancer, we examined the effects of co-inhibition of EGFR and EZH2 on 2 colon cancer cell lines, HT-29 and HCT-15. Co-inhibition of EZH2 and EGFR with the small molecules UNC1999 and gefitinib, led to a significant decrease in cell number and increased apoptosis compared to inhibition of either pathway alone, and similar results were noted after EZH2 shRNA knockdown. Moreover, co-inhibition of EZH2 and EGFR also significantly induced autophagy, indicating that autophagy may play a role in the observed synergy. Together, these findings suggest that inhibition of both EZH2 and EGFR serves as an effective method to increase the efficacy of EGFR inhibitors in suppressing colon cancer cells. 相似文献
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The methyltransferase EZH2 is not required for mammary cancer development,although high EZH2 and low H3K27me3 correlate with poor prognosis of ER‐positive breast cancers 下载免费PDF全文
Woo Kyun Bae Kyung Hyun Yoo Ji Shin Lee Young Kim Ik‐Joo Chung Min Ho Park Jung Han Yoon Priscilla A. Furth Lothar Hennighausen 《Molecular carcinogenesis》2015,54(10):1172-1180
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Dysregulation of protein methyltransferases in human cancer: An emerging target class for anticancer therapy 下载免费PDF全文
Protein methylation is one of the important post‐translational modifications. Although its biological and physiological functions were unknown for a long time, we and others have characterized a number of protein methyltransferases, which have unveiled the critical functions of protein methylation in various cellular processes, in particular, in epigenetic regulation. In addition, it had been believed that protein methylation is an irreversible phenomenon, but through identification of a variety of protein demethylases, protein methylation is now considered to be dynamically regulated similar to protein phosphorylation. A large amount of evidence indicated that protein methylation has a pivotal role in post‐translational modification of histone proteins as well as non‐histone proteins and is involved in various processes of cancer development and progression. As dysregulation of this modification has been observed frequently in various types of cancer, small‐molecule inhibitors targeting protein methyltransferases and demethylases have been actively developed as anticancer drugs; clinical trials for some of these drugs have already begun. In this review, we discuss the biological and physiological importance of protein methylation in human cancer, especially focusing on the significance of protein methyltransferases as emerging targets for anticancer therapy. 相似文献