zeste基因增强子同源物2在乳腺癌中的研究现状

zeste基因增强子同源物2(EZH2)是果蝇zeste基因增强子[E(z)]的人类同源物组蛋白甲基化的重要工具酶,也是多梳基因家族PcG(polycomb group)的核心成员。EZH2参与多梳蛋白复合体2的形成,促使相应组蛋白甲基化,从表观遗传学的角度介导相应靶基因沉默,在肿瘤的发生、发展过程中发挥着重要作用。其高表达与多种恶性肿瘤的发生、发展和极差的预后密切相关。近年来,越来越多的学者对EZH2的致癌机制进行了深入研究,为乳腺癌转移的检测、预后评估及治疗提供了全新的思路。笔者就EZH2表达情况及其与乳腺癌发生、发展、转移及预后之间的关系作一综述,以便临床医师更好地认识这一新的肿瘤标志物。     

EZH2基因在消化系统肿瘤中的研究进展

多梳抑制复合物2(PRC2)是一种作用于组蛋白H3赖氨酸位点K27的高度保守的组蛋白甲基转移酶,是PcG蛋白家族的一员.而PRC2的催化亚基是果蝇Zeste基因增强子同源物2(EZH2).大量研究证明,EZH2在多种肿瘤组织中高表达,例如乳腺癌、非小细胞肺癌、胃癌等.本文总结了EZH2基因的起源、结构、生物学功能及其在消化系统肿瘤中的研究进展,并对EZH2的靶向治疗进行展望.     

PTTG和EZH2在肝癌中的表达及其临床意义

[目的]分析垂体肿瘤转化基因(pituitarytumor-transforming gene,PTTG)和果蝇zeste基因增强子同源物2(enhancer of zeste homolog2,EZH2)在原发性肝细胞性肝癌(hepatocellular carcinoma,HCC)中的表达及其临床意义。[方法]应用免疫组化S-P法检测HCC50例、肝硬化30例、正常肝组织10例中PTTG、EZH2蛋白的表达。[结果]HCC、肝硬化和正常肝组织的PTTG蛋白阳性表达率分别是70.00%(35/50)、90.00%(27/30)、0(0/10),三者之间的差异有统计学意义(χ2=15.78,P<0.05),且PTTG蛋白在肝硬化中的表达明显高于在HCC中的表达(χ2=4.30,P<0.05);HCC、肝硬化和正常肝组织的EZH2蛋白阳性表达率分别是88.00%(44/50)、46.67%(14/30)、30.00%(3/10),三者之间的差异有统计学意义(χ2=20.63,P<0.05),且EZH2蛋白在HCC中的表达明显高于在肝硬化和正常肝组织中的表达(χ2=16.07,χ2=14.07,P<0.05)。[结论]PTTG和EZH2异常表达与HCC的发展密切相关,在HCC的发展过程中起重要的作用。     

EZH2与肿瘤的关系

果蝇zeste基因增强子同源物2（EZH2）通过催化组蛋白H3第27位赖氨酸三甲基化抑制基因表达。在前列腺癌、乳腺癌、膀胱癌及胃癌等多种肿瘤中都有高表达,与肿瘤的恶性进程、侵袭性、转移能力关系密切。随着对其在肿瘤中分子功能、上下游调控机制和临床病理特点的深入了解,EZH2有望做为靶点,为肿瘤治疗提供新的途径。     

EZH2在乳腺癌中的差异表达及临床意义

目的:利用整合生物信息学手段分析EZH2（enhancer of zeste 2 polycomb repressive complex 2 subunit）基因在乳腺癌中的表达及其临床意义。方法:在肿瘤基因组计划数据库（The Cancer Genome Atlas,TCGA）中下载乳腺癌与正常乳腺组织的基因表达谱数据,进一步利用Ualcan数据库和人类蛋白质图谱（The Human Protein Atlas）数据库数据分析EZH2基因在乳腺癌中的mRNA及蛋白表达水平。利用Ualcan数据库分析EZH2基因的甲基化水平并筛选其共表达基因;对EZH2及其共表达基因进行GO（Gene Ontology）富集分析和KEGG通路分析以明确EZH2的共表达基因参与的生物学过程和相关通路;使用Kaplan-Meier生存分析法分析乳腺癌患者的总生存期、无病生存期、无远处转移生存期及后进展生存期与EZH2基因表达水平的关系并绘制生存曲线。结果:与正常乳腺组织相比,EZH2在乳腺癌组织中的mRNA及蛋白表达量明显升高。而EZH2的甲基化程度在乳腺癌组织与正常乳腺组织中则差异不明显。同时,EZH2的表达水平与年龄、乳腺癌分期及乳腺癌分子分型等因素密切相关。EZH2及其共表达基因主要参与了核碱基的调节、细胞周期调控、染色体分离、DNA复制、DNA修复等生物学过程,并参与了细胞周期、DNA 复制、M/G1期转化、M期、有丝分裂前中期、ATM通路等生物学通路。此外,EZH2基因表达水平高的乳腺癌患者的总生存期、无病生存期、无远处转移生存期及后进展生存期均明显低于EZH2基因低表达的患者。结论:EZH2在乳腺癌组织中高表达并且与患者不良预后密切相关。同时,EZH2的表达水平与乳腺癌的发生、发展密切相关。EZH2在乳腺癌诊断、靶向治疗及预后分析中具有重要的临床意义。     

凋亡蛋白酶活化因子-1基因在贲门腺癌中的甲基化状态及其临床意义

目的:探讨贲门腺癌(gastric cardiac adenocarcinoma,GCA)中凋亡蛋白酶活化因子-1(apoptosis protease activating factor-1,Apaf-1)基因启动子区甲基化状态及其与果蝇zeste基因增强子人类同源物2(enhancer of zeste homolog 2,EZH2)蛋白表达之间的相关性.方法:应用甲基化特异性PCR(methylation specific polymerase chain reaction,MSP)检测GCA组织及癌旁组织中Apaf-1基因甲基化状态,应用免疫组织化学法检测GCA组织及癌旁组织中Apaf-1和EZH2蛋白的表达情况.结果:GCA组织中Apaf-1基因甲基化率显著高于癌旁组织[49.6％ (62/125)vs4.0％(5/125),P＜0.01],Ⅲ期和Ⅳ期GCA组织中Apaf-1基因甲基化率显著高于Ⅰ期和Ⅱ期(58.8％vs 38.6％,P＜0.05),但GCA组织中Apaf-1基因甲基化率与GCA的组织学分化程度无关(P＞0.05).GCA组织中Apaf-1蛋白表达阳性率显著低于相应癌旁组织(39.2％ vs 96.0％,P＜0.O1),且与Apaf-1基因甲基化状态相关.GCA组织中EZH2蛋白表达阳性率显著高于相应癌旁组织(74.4％vs 11.2％,P＜0.01),且与Apaf-1蛋白的表达呈负相关.结论:GCA组织中Apaf-1基因启动子区呈高甲基化,Apaf-1和EZH2蛋白可能共同参与了GCA的发展.     

zeste基因增强子同源物2在血液系统肿瘤中的研究进展

zeste基因增强子同源物2(EZH2)是一种组蛋白甲基转移酶, 在组蛋白甲基化修饰中研究较为广泛, 其可促进基因的表观遗传学基因沉默, 并通过多种调控机制介导肿瘤的发生。EZH2的功能获得和丧失突变在许多癌症中已被证实。目前, 随着EZH2在表观遗传机制中的调控作用得到广泛重视, EZH2失调影响血液系统恶性肿瘤发病机制的确切方式仍有待阐明。文章对EZH2在血液系统肿瘤中的致病作用进行综述, 以期为血液系统肿瘤的防治寻找新的靶点。     

EZH2和FHIT在肝癌中的表达及其临床意义

[目的]探讨果蝇zeste基因增强子同源物2(EZH2)和脆性组氨酸三联体(FHIT)蛋白在原发性肝细胞性肝癌(HCC)组织中的表达,及其在肝癌发生发展过程中的作用和临床病理学意义。[方法]应用免疫组化S-P法检测50例原发性肝细胞性肝癌、30例肝硬化、10例正常肝组织中EZH2、FHIT蛋白的表达。[结果]FHIT蛋白在HCC中的表达明显低于肝硬化和正常肝组织,阳性表达率分别是40.00%(20/50)、80.00%(24/30)、80.00%(8/10),三者之间具有明显的差异性(χ2=15.74,P<0.05);HCC、肝硬化和正常肝组织中EZH2蛋白阳性表达率分别是88.00%(44/50)、46.67%(14/30)、30.00%(3/10),三者之间的差异有统计学意义(χ2=20.63,P<0.05),且EZH2蛋白在HCC组织中的表达明显高于肝硬化和正常肝组织中的表达(χ2=16.07,χ2=14.07,P均<0.05)。[结论]EZH2蛋白在肝癌中的表达增加与FHIT蛋白相关,提示肝癌中EZH2蛋白与FHIT蛋白可能相互协调,促进肝癌的发生发展。12     

弥漫大B细胞淋巴瘤zeste基因增强子同源物2表达及其与临床病理特征和预后的关系

目的探讨弥漫大B细胞淋巴瘤(DLBCL)患者zeste基因增强子同源物2(EZH2)表达及其与临床病理特征和预后的关系。方法回顾性分析2009年1月至2018年12月山西省肿瘤医院有随访资料的106例DLBCL患者临床病理资料, 其中非生发中心B细胞型(non-GCB型)76例(72%), 生发中心B细胞型(GCB型)30例(28%), 以11例淋巴结反应性增生患者作为正常对照, 采用EnVision法检测EZH2、c-myc蛋白表达情况, 分析二者的相关性及EZH2蛋白与患者临床病理特征、总生存(OS)、无进展生存(PFS)的关系。结果 DLBCL患者中EZH2、c-myc蛋白阳性表达率分别为78.3%(83/106)与48.1%(51/106), 正常对照两者均不表达。non-GCB型中EZH2蛋白阳性表达率高于GCB型(P<0.01)。EZH2蛋白表达与临床分期、血清乳酸脱氢酶(LDH)水平、国际预后指数(IPI)评分均有关(均P<0.01)。GCB型中EZH2与c-myc蛋白表达呈正相关(r=0.74, P<0.001)。DLBCL中EZH2阴性组OS及PFS...     

FOXM1和EZH2在胶质瘤组织中的表达及其与预后的相关性

目的:探讨叉头框蛋白M1(forkhead box protein M1,FOXM1)和组蛋白甲基转移酶同源序列2增强子(enhancer of zeste 2 polycomb repressive complex 2 subunit,EZH2)在胶质瘤组织中的表达及二者的相关性,并分析其表达与患者预后的相关性。方法:利用数据集GSE4290、GSE7696获取FOXM1和EZH2在胶质瘤组织中的表达及其二者相关性。收集19例胶质瘤组和4例对照组样本,采用实时荧光定量聚合酶链反应（quantitative real time PCR,qPCR）和细胞基因干扰实验验证FOXM1和EZH2的表达水平和相关性。通过数据集GSE4412和GSE43378构建生存分析,阐明FOXM1和EZH2的表达与预后的相关性。结果:在数据集GSE4290、GSE7696中,FOXM1和EZH2在胶质瘤组织中存在明显上调,差异有统计学意义,且与新收集的胶质瘤组织样本表达结果一致;FOXM1和EZH2在数据集GSE4290、GSE7696、GSE4412和GSE43378中表达相关性系数r分别为0.777 4、0.878 9、0.860 2和0.825 1;此外,生存分析显示,FOXM1和EZH2高表达与较差预后相关,差异有统计学意义。结论:FOXM1和EZH2在胶质瘤组织中高表达,两者具有相关性,且高表达与较差预后相关。     

EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with an undifferentiated status and generally poor prognosis, but the basis for these characteristics remains unknown. In this study, we show that upregulation of the Polycomb protein histone methyltransferase EZH2, which limits differentiation in many tissues, is critical to maintain the undifferentiated state and poor prognostic status of NB by epigenetic repression of multiple tumor suppressor genes. We identified this role for EZH2 by examining the regulation of CASZ1, a recently identified NB tumor suppressor gene whose ectopic restoration inhibits NB cell growth and induces differentiation. Reducing EZH2 expression by RNA interference-mediated knockdown or pharmacologic inhibiton with 3-deazaneplanocin A increased CASZ1 expression, inhibited NB cell growth, and induced neurite extension. Similarly, EZH2(-/-) mouse embryonic fibroblasts (MEF) displayed 3-fold higher levels of CASZ1 mRNA compared with EZH2(+/+) MEFs. In cells with increased expression of CASZ1, treatment with histone deacetylase (HDAC) inhibitor decreased expression of EZH2 and the Polycomb Repressor complex component SUZ12. Under steady-state conditions, H3K27me3 and PRC2 components bound to the CASZ1 gene were enriched, but this enrichment was decreased after HDAC inhibitor treatment. We determined that the tumor suppressors CLU, NGFR, and RUNX3 were also directly repressed by EZH2 like CASZ1 in NB cells. Together, our findings establish that aberrant upregulation of EZH2 in NB cells silences several tumor suppressors, which contribute to the genesis and maintenance of the undifferentiated phenotype of NB tumors.     

Synergistic antileukemic action of a combination of inhibitors of DNA methylation and histone methylation

DNA methylation and histone methylation are both involved in epigenetic regulation of gene expression and their dysregulation can play an important role in leukemogenesis. Aberrant DNA methylation has been reported to silence the expression of tumor suppressor genes in leukemia. Overexpression of the histone methyltransferase, EZH2, a subunit of the polycomb group repressive complex 2 (PRC2), was observed to promote oncogenesis. This is due to aberrant gene silencing by the trimethylation of histone H3 lysine 27 (H3K27me3) by EZH2. Since both these epigenetic silencing events are reversible, they are interesting targets for chemotherapeutic intervention by using an inhibitor of DNA methylation, such as 5-aza-2'-deoxcytidine (5-AZA-CdR), and 3-deazaneplanocin-A (DZNep), an inhibitor of the EZH2. Human HL-60 and murine L1210 leukemic cells exposed in vitro to 5-AZA-CdR and DZNep in combination showed a synergistic loss of clonogenicity in a colony assay as compared to each agent alone. This positive chemotherapeutic interaction was also observed in mice with L1210 leukemia. Quantitative PCR showed that the combination also produced a remarkable synergistic activation of the tumor suppressor genes, CDKN1A and FBXO32. Microarray analysis showed that 5-AZA-CdR plus DZNep produced a synergistic activation of >150 genes. Our results indicate that 5-AZA-CdR plus DZNep can reactivate target genes that are silenced by two distinct epigenetic mechanisms leading to a loss of the proliferative potential of leukemic cells.     

Zeste增强子同源物2与肿瘤转移的研究进展

转移是癌症患者死亡和预后不良的主要原因,阐明肿瘤转移机制对改善患者预后至关重要.Zeste增强子同源物2(enhancer of zeste homolog 2,EZH2)是多梳蛋白家族(Polycomb group,PcG)的重要成员,其广泛参与调节多种细胞生理过程,如细胞迁移、细胞周期、细胞增殖、细胞凋亡、DNA损...     

Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes

Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2-/Ki67low, ER+/HER2-/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer.