The Role of EZH2 in Non-Muscle Invasive Bladder Cancer

膀胱癌是男性第四大常见癌症，也是退伍军人和VHA的重大负担 由于与吸烟和暴露于部署有关的复发和进展的频率很高， 相关的致癌物质。近80%的膀胱癌不侵犯膀胱壁的肌肉（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到肌肉 浸润伴淋巴结转移导致30%的患者死亡。死亡的主要原因是 膀胱癌对治疗有抗性，因为这些浸润性癌获得细胞可塑性和干细胞， 比如财产鉴定调节细胞分化中这种变化的机制 表型是癌症的标志，并且是由基因突变和 表观遗传细胞重编程我们研究的长期目标是研究分子和 表观遗传途径驱动膀胱癌的侵袭。通过了解这些机制，我们可以开发 为膀胱癌患者提供合理、新颖的治疗方法。为了研究表观遗传机制， 作为膀胱癌的可行靶点，我们评估了组蛋白 Zeste-2（EZH 2）的甲基转移酶增强子，作为多梳阻遏物复合物-2（PRC-2）的一部分， 膀胱癌我们的初步数据表明EZH 2及其组蛋白靶点的表达增加， H3 K27 me 3，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，EZH 2表达增加。中华人民共和国的不稳定-2 复合物阻止细胞增殖。与我们的研究结果一致，多个人类 膀胱癌数据库表明EZH 2在浸润性膀胱癌中过表达，我们 已经在膀胱癌患者的肿瘤标本中得到证实。根据这些初步数据， 我们的中心假设是EZH 2通过引起组蛋白的整体变化来驱动膀胱癌的侵袭。 甲基化，通过上皮细胞的甲基化将细胞身份转变为侵袭性和干细胞样表型， 间质转化因此，鉴于我们有希望的初步数据，我们建议调查我们的假设 1）确定EZH 2在膀胱癌发生和发展中的作用; 2） 通过EZH 2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; 评价EZH 2作为膀胱癌治疗的药理学抑制。目前，我们没有 膀胱癌的个性化遗传或表观遗传靶点，以及我们对非肌肉浸润性膀胱癌的最佳治疗 膀胱癌发病年龄> 40岁。通过多学科合作，我们证明了可行性 我们的方法。成功完成本建议中所述的研究将提供一个创新的 研究膀胱癌侵袭机制和利用新的 膀胱癌的治疗方法。这些靶向EZH 2的药物克服了细胞免疫的挑战。 耐药性和临床前调查，将允许访问退伍军人与膀胱癌。

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.