The Role of EZH2 in Non-Muscle Invasive Bladder Cancer

EZH2 在非肌层浸润性膀胱癌中的作用

• 批准号: 9241048
• 负责人: Joshua James Meeks
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241048
• 关键词: Accounting; Address; Affect; Aggressive course; Automobile Driving; Bioinformatics; Bladder; Bladder Neoplasm; Cancer Etiology; Cancer Model; Cancer cell line; Carcinogens; Carcinoma; Cause of Death; Cell Proliferation; Cells; Cessation of life; Chromatin; Complex; DNA Sequence Alteration; Data; Databases; Development; Diagnosis; Enhancers; Epigenetic Process; Exposure to; Frequencies; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Global Change; Goals; Histones; Human; Interdisciplinary Study; Investigation; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Metastatic Neoplasm to Lymph Nodes; Methylation; Modeling; Molecular; Mus; Muscle; Mutation; Occupational Exposure; Pathway interactions; Patient risk; Patients; Pharmacology; Phenotype; Polycomb; Process; Proliferating; Property; Proteins; Recurrence; Regulator Genes; Repression; Research; Resistance; Risk; Role; Smoking; Specimen; Stem cells; Therapeutic; Tissue Microarray; Transcription Initiation Site; Transferase; Transitional Cell Carcinoma; Urothelial Cell; Veterans; actionable mutation; base; cancer cell; cancer initiation; cancer invasiveness; chromatin immunoprecipitation; chromatin remodeling; clinical investigation; cost; epithelial to mesenchymal transition; gene repression; high risk; histone methylation; histone methyltransferase; in vivo Model; inhibitor/antagonist; innovation; knock-down; men; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; personalized medicine; pre-clinical; protein expression; stem-like cell; targeted agent; targeted treatment; therapeutic development; therapeutic target; therapy resistant; tumor; tumor initiation; tumor progression

Bladder cancer is the fourth most common cancer in men and a significant burden for Veterans and the VHA due to the high frequency of recurrence and progression linked to smoking and exposure to deployment- related carcinogens. Nearly 80% of bladder cancers do not invade the muscle of the bladder wall (called “non- muscle invasive bladder cancer”, NMIBC) but the most aggressive of these tumors will progress to muscle invasion with lymph node metastasis resulting in death in 30% of patients. The primary cause of death from bladder cancer is resistance to therapy as these invasive carcinomas acquire cellular plasticity and stem cell- like properties. Identification of mechanisms that regulate this change in cellular differentiation This invasive phenotype is a hallmark of cancer and a major shift in differentiation regulated by both genetic mutations and epigenetic cellular reprogramming. The long-term goal of our research is to investigate the molecular and epigenetic pathways driving invasion of bladder cancer. By understanding these mechanisms, we may develop rational and novel therapeutics for patients with bladder cancer. To investigate the epigenetic mechanisms that contribute to invasion and proliferation as a feasible target for bladder cancer, we evaluated the histone methyltransferase Enhancer of Zeste-2 (EZH2), as part of the polycomb repressor complex-2 (PRC-2) in bladder cancer. Our preliminary data demonstrate increased expression of EZH2 and its histone target, H3K27me3, in a carcinogen-induced mouse model of bladder cancer. In multiple bladder cancer cell lines, EZH2 expression is increased compared to non-transformed urothelial cells. Destabilization of the PRC-2 complex stops cellular proliferation. Consistent with our findings, bioinformatics analysis of multiple human bladder cancer databases demonstrate that EZH2 is overexpressed in invasive bladder cancers, which we have confirmed in tumor specimens from patients with all stages of bladder cancer. Given this preliminary data, our central hypothesis is that EZH2 drives invasion of bladder cancer by causing global changes in histone methylation that shifts cellular identity to an invasive and stem cell-like phenotype via an epithelial to mesenchymal transition. Thus, given our promising preliminary data, we propose to investigate our hypothesis with the following Specific Aims: 1) Determine the role of EZH2 in bladder cancer initiation and progression; 2) Investigate aberrant histone methylation of EMT, invasive and stem cell genes by EZH2 in bladder cancer; 3) Evaluate pharmacologic inhibition of EZH2 as a treatment for bladder cancer. Currently, we have no personalized genetic or epigenetic targets for bladder cancer and our best therapy for non-muscle invasive bladder cancer is > 40 years old. Through multi-disciplinary collaboration we have demonstrated feasibility with our approach. Successful completion of the studies described in this proposal will provide an innovative approach to both investigate the mechanisms involved in the invasion of bladder cancer and utilize a novel therapeutic approach to treat bladder cancer. These EZH2-targeted agents overcome the challenge of cellular resistance and have pre-clinical investigations that will allow access to Veterans with bladder cancer.

膀胱癌是男性中第四大癌症，对退伍军人和VHA的烧伤很大 由于复发的频率高和与吸烟相关的进展，并与部署相关 - 相关致癌物。近80％的膀胱癌不会侵入膀胱壁的肌肉（称为“非 - 肌肉侵入性膀胱癌”，NMIBC），但这些肿瘤中最具侵略性的肌肉会发展为肌肉 淋巴结转移的浸润导致30％的患者死亡。死亡的主要原因 膀胱癌是对治疗的抗药性，因为这些浸润性癌获得了细胞可塑性和干细胞 - 喜欢属性。鉴定调节细胞分化变化的机制这种侵入性 表型是癌症的标志，是基因突变和分化的主要变化 表观遗传细胞重编程。我们研究的长期目标是研究分子和 表观遗传途径推动了膀胱癌的侵袭。通过了解这些机制，我们可能会发展 膀胱癌患者的理性和新型治疗。调查表观遗传机制 我们有助于入侵和增殖作为膀胱癌的可行靶标，我们评估了组蛋白 Zeste-2（EZH2）的甲基转移酶增强酶，作为Polycomb复制器复合物-2（PRC-2）的一部分 膀胱癌。我们的初步数据表明EZH2及其Hisstone目标的表达增加了 H3K27me3，在致癌物诱导的膀胱癌小鼠模型中。在多个膀胱癌细胞系中， 与未转化的尿路上皮细胞相比，EZH2表达增加。 PRC-2的不稳定 复合物可以停止细胞增殖。与我们的发现一致，对多人的生物信息学分析 膀胱癌数据库表明EZH2在侵入性膀胱癌中过表达，我们 已经在所有膀胱癌所有阶段的患者的肿瘤标本中证实。鉴于此初步数据 我们的中心假设是EZH2通过引起组蛋白的全球变化来驱动膀胱癌 甲基化将细胞身份转移到侵入性和干细胞样表型中的甲基化。 间充质转变。鉴于我们承诺的初步数据，我们建议研究我们的假设 以以下特定目的：1）确定EZH2在膀胱癌倡议和进展中的作用； 2） 通过EZH2在膀胱癌中研究EMT，侵入性和干细胞基因的异常组蛋白甲基化； 3） 评估对EZH2的药物抑制作用作为膀胱癌的治疗方法。目前，我们没有 膀胱癌的个性化遗传或表观遗传靶标，以及我们对非肌肉侵入性的最佳疗法 膀胱癌> 40岁。通过多学科合作，我们证明了可行性 以我们的方法。成功完成本提案中描述的研究将提供创新的 两种方法都研究了侵入膀胱癌的机制，并利用了一种新颖 治疗膀胱癌的治疗方法。这些针对EZH2的剂克服了细胞的挑战 抵抗力并进行临床前研究，可以进入患有膀胱癌的退伍军人。