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到间充质转变（EMT）发育遗传程序的启动有关。 EMT的基本标志是抑制EMT网守E-钙粘着蛋白，随后丧失了上皮性能，例如立方体上皮形态。这与细胞转化为间充质特征，包括蛋白水解活性，明显增加了细胞运动，浸润和转移性 行为。因此，E-钙粘着蛋白的表达及其对上皮连接络合物的调节对于维持细胞 - 细胞接触，上皮极性和限制肿瘤传播至关重要。 EMT受协调的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型抑制剂复合物的成分的上调，例如Zeste同源物2（EZH2）的增强子，与预后不良相关。 EZH2过表达是PCA中广泛发生的，并被提议有助于治疗失败和致死性。 EZH2是一种组蛋白甲基转移酶，介导抑制肿瘤抑制基因以促进促肿瘤遗传概况。 EZH2已被证明可以抑制E-钙粘蛋白并促进EMT事件，这表明这是其致癌活性的关键机制。尽管EZH2作为癌症进展的介体的作用是众所周知的，但调节其表达的肿瘤分泌因素尚不清楚。我们最近表明，细胞外HSP90（EHSP90）是EMT事件的新型发起者。临床上，在患有各种原发性和转移性癌症（包括PCA）的患者血清中优先检测到EHSP90。此外，EHSP90在临床前肿瘤模型中似乎是关键的促次转移因子。尤其， EHSP90抑制E-钙粘蛋白的表达和功能，促进间充质形态，并增加细胞运动性和蛋白水解活性。我最近发现，EHSP90在ERK依赖性信号通路中上调EZH2表达，令人惊讶的是，ERK信号传导和EZH2表达对于EHSP90介导的E-Cadherin抑制至关重要。通过发现EHSP90促进EZH2募集到E-Cadherin Reporter的发现证明了EHSP90颠覆EZH2功能的进一步证据，这表明了E-Cadherin抑制的机械基础。因此，我们假设EHSP90通过激活ERK促进PCA肿瘤的进展，EZH2的上调和抑制E-钙粘着蛋白，从而启动肿瘤EMT事件。为了检验这一假设，我将确定EHSP90如何上调EZH2并改变其募集以促进体外和体内前列腺癌中的肿瘤发生和转移。这些研究将要求我发展各种技术技能，并与各个领域的专家合作。这项培训促进了我作为独立研究人员的发展，并为我的学术研究职业做好了准备。