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.

膀胱癌是男性第四大常见癌症，对退伍军人和 VHA 来说是一个重大负担 由于与吸烟和暴露于部署相关的复发和进展频率很高- 近 80% 的膀胱癌不会侵入膀胱壁肌肉（称为“非膀胱癌”）。 肌肉浸润性膀胱癌”，NMIBC），但这些肿瘤中最具侵袭性的将进展为肌肉 侵袭伴淋巴结转移导致30%患者死亡的主要原因。 膀胱癌对治疗具有抵抗力，因为这些浸润性癌获得了细胞可塑性和干细胞- 鉴定调节细胞分化这种侵入性变化的机制。 表型是癌症的一个标志，也是由基因突变和基因突变调节的分化的重大转变。 我们研究的长期目标是研究表观遗传细胞重编程。 通过了解这些机制，我们可以开发驱动膀胱癌侵袭的表观遗传途径。 膀胱癌患者的合理和新颖的治疗方法研究其表观遗传机制。 作为膀胱癌的可行靶点，有助于侵袭和增殖，我们评估了组蛋白 Zeste-2 (EZH2) 的甲基转移酶增强剂，作为多梳阻遏物复合体 2 (PRC-2) 的一部分 我们的初步数据表明 EZH2 及其组蛋白靶标的表达增加， H3K27me3，在致癌物诱导的膀胱癌小鼠模型中，在多种膀胱癌细胞系中， 与未转化的尿路上皮细胞相比，EZH2 表达增加 PRC-2 的不稳定。 与我们的研究结果一致，对多个人类的生物信息学分析。 膀胱癌数据库表明 EZH2 在浸润性膀胱癌中过度表达，我们对此进行了研究 鉴于这些初步数据，已在所有阶段的膀胱癌患者的肿瘤标本中得到证实。 我们的中心假设是 EZH2 通过引起组蛋白的整体变化来驱动膀胱癌的侵袭 甲基化通过上皮细胞将细胞身份转变为侵袭性和干细胞样表型 因此，鉴于我们有希望的初步数据，我们建议研究我们的假设。 具有以下具体目标：1) 确定 EZH2 在膀胱癌发生和进展中的作用；2) 通过 EZH2 研究膀胱癌中 EMT、侵袭性和干细胞基因的异常组蛋白甲基化 3) 评估 EZH2 的药理学抑制作为膀胱癌的治疗方法目前，我们还没有。 膀胱癌的个性化遗传或表观遗传靶标以及我们针对非肌肉侵入性的最佳疗法 通过多学科合作，我们已经证明了膀胱癌的可行性。 通过我们的方法，成功完成本提案中描述的研究将提供创新。 方法既研究膀胱癌侵袭的机制，又利用一种新的方法 这些 EZH2 靶向药物克服了细胞的挑战。 耐药性并进行临床前研究，以便接触患有膀胱癌的退伍军人。