Role of EZH2 in Extracellular Hsp90 Mediated Prostate Cancer Tumorigenesis

EZH2 在细胞外 Hsp90 介导的前列腺癌肿瘤发生中的作用

• 批准号: 8520721
• 负责人: Krystal Dole Nolan
• 金额: $ 4.22万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520721
• 关键词: 3' Untranslated Regions; Affect; Apoptosis; Behavior; Binding; Biological Assay; Cancer Etiology; Cell Maintenance; Cells; Cessation of life; Clinical; Complex; Data; Development; Disease; Disseminated Malignant Neoplasm; E-Cadherin; Epigenetic Process; Epithelial; Event; Fellowship; Fostering; Frequencies; Gatekeeping; Gene Targeting; Genes; Genetic Programming; Genetic Transcription; Goals; In Vitro; Lead; Light; Luciferases; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Mesenchymal; MicroRNAs; Modeling; Molecular Target; Monitor; Morphology; Nature; Neoplasm Metastasis; Pathway interactions; Patients; Phenotype; Plasmids; Polycomb; Pre-Clinical Model; Process; Property; Regulation; Reporter; Research; Research Personnel; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Testing; Therapeutic; Training; Transcript; Treatment Failure; Tumor Promotion; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Up-Regulation; Work; base; bench to bedside; career; cell motility; chromatin immunoprecipitation; chromatin remodeling; clinically relevant; developmental genetics; epithelial to mesenchymal transition; extracellular; genetic profiling; histone methyltransferase; human EZH2 protein; in vivo; men; neoplastic cell; novel; novel therapeutics; outcome forecast; overexpression; pre-clinical; programs; promoter; protein expression; public health relevance; skills; trend; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Cancer metastasis associated with the progression of prostate cancer (PCa) is the second leading cause of cancer death in men. Metastatic progression is commonly associated with initiation of the epithelial to mesenchymal transition (EMT) developmental genetic program. A fundamental hallmark of EMT is the suppression of the EMT gatekeeper E-cadherin, and subsequent loss of epithelial properties such as cuboidal epithelial morphology. This occurs concomitant with a cellular conversion towards mesenchymal features including proteolytic activity, markedly increased cell motility, invasion, and metastatic behavior. Thus, the expression of E-cadherin, and its regulation of epithelial junctional complexes, is critical for the maintenance of cell-cell contact, epithelial polarity, and for restraining tumor dissemination. EMT is regulated by coordinated signaling and epigenetic events. In particular, upregulation of components of the chromatin remodeling polycomb repressor complexes in metastatic cancers, such as Enhancer of Zeste Homolog 2 (EZH2), correlates with poor prognosis. EZH2 overexpression is a widespread occurrence in PCa and is proposed to contribute to treatment failure and lethality. EZH2 is a histone methyltransferase that mediates the suppression of tumor suppressor genes to facilitate a pro-tumorigenic genetic profile. EZH2 has been shown to both suppress E-cadherin and to promote EMT events, indicating this as one key mechanism for its tumorigenic activity. Although the role of EZH2 as a mediator of cancer progression is well known, the tumor secreted factors regulating its expression remain unknown. We have recently shown that extracellular Hsp90 (eHsp90) is a novel initiator of EMT events. Clinically, eHsp90 is preferentially detected in patient serum from those afflicted with various primary and metastatic cancers, including PCa. Additionally, eHsp90 appears to function as a critical pro-metastatic factor in preclinical tumor models. In particular, eHsp90 suppresses E-cadherin expression and function, promotes a mesenchymal morphology, and increases cell motility and proteolytic activity. I have recently found that eHsp90 upregulates EZH2 expression in an ERK-dependent signaling pathway, and strikingly, both ERK signaling and EZH2 expression are essential for eHsp90 mediated suppression of E-cadherin. Further evidence that eHsp90 subverts EZH2 function is demonstrated by the finding that eHsp90 promotes the recruitment of EZH2 to the E-cadherin reporter, indicating a mechanistic basis for E-cadherin suppression. We therefore hypothesize that eHsp90 promotes PCa tumor progression via activation of ERK, upregulation of EZH2 and suppression of E-cadherin, thereby initiating tumorigenic EMT events. To test this hypothesis, I will determine how eHsp90 upregulates EZH2 and alters its recruitment to promote tumorigenesis and metastasis in prostate cancer both in vitro and in vivo. These studies will require me to develop a diverse range of technical skills and collaborate with experts in various fields. This training wll foster my development as an independent researcher and prepare me for a career in academic research.

描述（由申请人提供）：与前列腺癌（PCa）进展相关的癌症转移是男性癌症死亡的第二大原因。转移进展通常与上皮间质转化（EMT）发育遗传程序的启动相关。 EMT 的一个基本标志是 EMT 看门人 E-钙粘蛋白的抑制，以及随后的上皮特性（例如立方上皮形态）的丧失。这种情况与细胞向间充质特征的转化同时发生，包括蛋白水解活性、细胞运动性显着增加、侵袭和转移 行为。因此，E-钙粘蛋白的表达及其对上皮连接复合物的调节对于维持细胞间接触、上皮极性和抑制肿瘤扩散至关重要。 EMT 受到协调信号传导和表观遗传事件的调节。特别是，转移性癌症中染色质重塑多梳阻遏复合物成分的上调，例如 Zeste 同源物增强剂 2 (EZH2)，与不良预后相关。 EZH2 过度表达在 PCa 中广泛存在，并被认为是导致治疗失败和致死的原因。 EZH2 是一种组蛋白甲基转移酶，可介导抑癌基因的抑制，从而促进促肿瘤基因谱。 EZH2 已被证明可以抑制 E-钙粘蛋白并促进 EMT 事件，表明这是其致瘤活性的一个关键机制。尽管 EZH2 作为癌症进展介质的作用众所周知，但调节其表达的肿瘤分泌因子仍然未知。我们最近证明细胞外 Hsp90 (eHsp90) 是 EMT 事件的新型启动子。临床上，eHsp90优先在患有各种原发性和转移性癌症（包括PCa）的患者血清中检测到。此外，eHsp90 似乎在临床前肿瘤模型中充当关键的促转移因子。尤其， eHsp90 抑制 E-钙粘蛋白的表达和功能，促进间充质形态，并增加细胞运动和蛋白水解活性。我最近发现 eHsp90 在 ERK 依赖性信号传导途径中上调 EZH2 表达，引人注目的是，ERK 信号传导和 EZH2 表达对于 eHsp90 介导的 E-钙粘蛋白抑制至关重要。 eHsp90 促进 EZH2 招募到 E-钙粘蛋白报告基因的发现证明了 eHsp90 破坏 EZH2 功能的进一步证据，表明 E-钙粘蛋白抑制的机制基础。因此，我们假设 eHsp90 通过激活 ERK、上调 EZH2 和抑制 E-钙粘蛋白来促进 PCa 肿瘤进展，从而启动致瘤性 EMT 事件。为了验证这一假设，我将确定 eHsp90 如何上调 EZH2 并改变其招募，以在体外和体内促进前列腺癌的肿瘤发生和转移。这些研究需要我发展各种技术技能并与各个领域的专家合作。这次培训将促进我作为独立研究员的发展，并为我从事学术研究职业做好准备。