EZH2在脑胶质瘤发生发展中作用机制研究进展

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...     

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-miR-139-5p通路在大肠癌中的表达及对化疗耐药性的影响

[目的]探讨EZH2-miR-139-5p通路在大肠癌中的表达及对化疗耐药性的影响.[方法]选取54例大肠癌患者癌组织及癌旁组织,比较癌组织和癌旁组织EZH2及miR-139-5p mRNA水平,并分析大肠癌组织中EZH2 mRNA与miR-139-5p mRNA水平的相关性.选取6种大肠癌细胞株(LOVO、RKO、H...     

EZH2和Ki-67蛋白在腺样囊性癌中的表达及其临床意义

  目的  研究人涎腺腺样囊性癌组织中EZH2（enhancer of zeste homolog2）和Ki-67的表达及其相关性。  方法  采用免疫组织化学染色法,检测石蜡包埋的42例涎腺腺样囊性癌（salivary adnoid cystic carcinoma,SACC）及5例正常涎腺组织中,多梳组蛋白EZH2和细胞周期蛋白Ki-67的表达水平,分析与临床病理特征之间的关系并探讨二者的相关性。  结果  EZH2在腺样囊性癌组织中的表达显著高于正常涎腺组织（P＜0.05）,EZH2表达阳性率66.67%（28/42）,EZH2表达与肿瘤病理分型及临床分期相关,而与性别、年龄、发病部位不相关,而在5例正常涎腺组织中不表达。在Ki-67阳性的33例腺样囊性癌患者中,25例EZH2表达阳性,表达率75.76%（25/33）,Ki-67阴性表达的9例中,3例EZH2表达阳性,表达率33.33%（3/9）,两者比较差异有统计学意义（P＜0.05）。  结论  EZH2在腺样囊性癌中表达增加且与肿瘤细胞的增殖密切相关,提示腺样囊性癌中EZH2通过其在细胞周期管理中的作用,参与肿瘤细胞的增殖过程。      

JMJD3和EZH2在45例喉鳞状细胞癌中的表达及其临床意义分析

摘 要：［目的］ 研究JMJD3及EZH2在喉鳞状细胞癌中的表达及其临床意义。［方法］ 收集45例喉鳞状细胞癌患者的喉癌、癌旁组织切片及相关临床特征数据,采用免疫组化染色法检测标本。采用?字2检验或Fisher确切概率法分析JMJD3与EZH2在喉鳞状细胞癌中的表达及其与临床特征的相关性。Kaplan-Meier分析JMJD3及EZH2与喉鳞状细胞癌3年总生存率的关联。［结果］ JMJD3及EZH2在喉癌组织中表达阳性率明显高于癌旁组织（?字2=9.800、10.766,P均<0.01）。在喉癌组织中,JMJD3及EZH2的表达与患者肿瘤分化程度、肿瘤部位、淋巴结转移、临床分期相关。JMJD3阳性表达及阴性表达患者的3年生存率分别为68.2%、87.0%（?字2=2.631,P=0.105）;EZH2阳性表达及阴性表达患者的3年生存率分别为70.8%、85.7%（?字2=1.688,P=0.194）。JMJD3和EZH2在喉癌中的表达呈正相关（P=0.02）。［结论］ 在喉鳞状细胞癌中JMJD3和EZH2均起了促癌基因的作用。JMJD3及EZH2的高表达与喉鳞状细胞癌的发生、转移、恶性程度存在显著关联,两者的失衡共同促进了喉癌的发生发展。     

HOTAIR mRNA和EZH2 mRNA在肾细胞癌组织中的表达情况

目的 探讨HOTAIR mRNA和EZH2 mRNA在肾细胞癌组织中的表达情况.方法 选取行手术切除的经病理学检查确诊的肾细胞癌患者的肾细胞癌组织标本61例,同时选取对应的癌旁正常肾组织标本61例为对照;采用逆转录-聚合酶链式反应(RT-PCR)检测肾细胞癌组织和癌旁正常肾组织中HOTAIR mRNA和EZH2 mRNA的表达水平.结果 肾细胞癌组织中HOTAIR mRNA和EZH2 mRNA的相对表达量均明显高于癌旁正常肾组织(P﹤0.01);不同临床分期、淋巴结转移情况肾细胞癌患者的肾细胞癌组织中HOTAIR mRNA和EZH2 mRNA的相对表达量比较,差异均有统计学意义(P﹤0.01);肾细胞癌组织中HOTAIR mRNA的相对表达量为(0.76±0.20),EZH2 mRNA的相对表达量为(2.04±0.51),两者呈正相关(r=0.683,P﹤0.01).结论 HOTAIR mRNA和EZH2 mRNA在肾细胞癌组织中的表达水平明显高于癌旁正常肾组织,检测肾细胞癌患者的HOTAIR、EZH2水平对其肿瘤的恶性程度判断具有一定参考价值.     

miR-4465调控EZH2的表达抑制胃癌细胞增殖、侵袭和迁移的机制探讨

目的:探讨miR-4465通过调控EZH2的表达对胃癌细胞增殖、侵袭和迁移的影响。方法:qRT-PCR检测胃癌组织和细胞系中miR-4465的表达水平;在MKN45细胞中过表达miR-4465或沉默EZH2,采用CCK-8和Transwell检测MKN45细胞增殖活力、迁移和侵袭能力;Western blotting检测EZH2、E-cadherin、N-cadherin和Vimentin的表达情况;双荧光素酶报告基因检测miR-4465与EZH2的相互作用。结果:与癌旁组织相比,miR-4465在胃癌组织中的表达降低,在胃癌细胞系(MCC-803、SGC7901、MKN45)中的表达水平显著低于人永生化胃细胞RGM-1,且在MKN45细胞系中的表达低于其他细胞。过表达miR-4465明显抑制MKN45细胞增殖、迁移、侵袭和上皮间质转化(epithelial-mesenchymal transition, EMT);双荧光素酶报告基因结果证实,miR-4465直接靶向作用于EZH2的3’-UTR;进一步实验证明,同时沉默miR-4465和EZH2能够恢复沉默EZH2对MKN45细胞增殖...     

EZH2在肝细胞性肝癌中的表达及其对HepG2增殖作用的研究

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。     

EZH2与VEGF在外阴鳞癌组织中的表达及临床意义

目的:探讨EZH2与VEGF在外阴鳞癌中的表达情况及两者与外阴鳞癌临床病理特征的关系。方法:采用免疫组化法对43例外阴鳞癌患者组织,30例外阴上皮内瘤变（VIN II-III）和10例外阴癌病灶外正常组织中的EZH2与VEGF蛋白表达进行测定。结果:外阴鳞癌组织中EZH2与VEGF的阳性率均高于VIN II-III组织及癌旁正常组织,三者间差异有统计学意义（P＜0.05）。EZH2与VEGF在外阴鳞癌中的表达与临床分期、病理分级、有无淋巴结转移有关（P均<0.05)。相关性分析显示,EZH2与VEGF在外阴鳞癌中的表达呈正相关（P＜0.05）。结论:EZH2与VEGF异常表达与外阴鳞癌发生和进展密切相关,其机制可能与二者协同促进肿瘤血管生成有关。     

磷酸化EZH2在头颈部鳞癌中的表达特征及对化疗敏感性的影响

目的：探究头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)中磷酸化Zeste同源增强子(enhancer of Zeste homolog 2,EZH2)的表达特征及对化疗敏感性的影响。方法：选取2018年1月至2021年3月天津医科大学肿瘤医院HNSCC患者组织标本及临床资料53例。免疫组织化学染色分析HNSCC组织标本中p-EZH2^S21、p-STAT3^Y705、HIF-1α和Ki-67的表达水平。Western blot检测HNSCC组织和细胞株中p-EZH2^S21的表达情况。在HNSCC细胞中构建EZH2野生型(EZH2-WT)和EZH2 S21位点突变(EZH2-S21A)的稳转细胞,CCK8实验和平板克隆实验检测EZH2以及S21位点磷酸化对HNSCC细胞增殖能力及其对顺铂(cisplatin,DDP)和5-氟尿嘧啶(5-fluorouracil,5-FU)敏感性的影响。结果：HNSCC中p-EZH2^S21表达升高,并且与p-ST...     

EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells

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.     

In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer

Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p?2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p?相似文献   

Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells

Overexpression of enhancer of zeste homolog 2 (EZH2), an epigenetic repressor, occurs in various malignancies and is associated with poor prognosis; however, the functional role of EZH2 overexpression in cancer versus non-cancerous tissue remains unclear. In this study, we found an inverse correlation between EZH2 and E-cadherin gene expression in gastric cancer cells. Knockdown of EZH2 by short interfering RNA in gastric cancer cells resulted in a restoration of the E-cadherin gene. We showed that the EZH2 complex existed with histone H3 and Lys27, which were methylated on E-cadherin promoter regions in gastric cancer cells. The restoration of E-cadherin was not involved in the change of the DNA methylation status in the E-cadherin promoter region. Immunofluorescence staining confirmed the expression of E-cadherin protein present in the cell membrane was restored after knockdown of EZH2, resulting in changing the cancer phenotype, such as its invasive capacity. In vivo , the relationship of inverse expression between EZH2 protein and E-cadherin protein was observed at the individual cellular level in gastric cancer tissue. This study provides into the mechanisms underlying the functional role of EZH2 overexpression in gastric cancer cells and a new modality of regulation of E-cadherin expression in silencing mechanisms of tumor suppressor genes. Our present study paves the way for exploring the blockade of EZH2 overexpression as a novel approach to treating cancer. ( Cancer Sci 2008; 99: 738–746)     

Coordinated regulation of polycomb group complexes through microRNAs in cancer

Polycomb Repressive Complexes (PRC1 and PRC2)-mediated epigenetic regulation is critical for maintaining cellular homeostasis. Members of Polycomb Group (PcG) proteins including EZH2, a PRC2 component, are upregulated in various cancer types, implicating their role in tumorigenesis. Here, we have identified several microRNAs (miRNAs) that are repressed by EZH2. These miRNAs, in turn, regulate the expression of PRC1 proteins BMI1 and RING2. We found that ectopic overexpression of EZH2-regulated miRNAs attenuated cancer cell growth and invasiveness, and abrogated cancer stem cell properties. Importantly, expression analysis revealed an inverse correlation between miRNA and PRC protein levels in cell culture and prostate cancer tissues. Taken together, our data have uncovered a coordinate regulation of PRC1 and PRC2 activities that is mediated by miRNAs.     

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.     

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Prostate cancer (PCa) is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem- and nonstem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the polycomb repressive complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2-dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients’ tumors and PCa cell lines, and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to an increase of aldehyde dehydrogenase (ALDH)-positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3-Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.