Polycomb -Independent Functions of EZH2 in Castration Resistant Prostate Cancer

EZH2 在去势抵抗性前列腺癌中的多梳独立功能

基本信息

批准号：
8700823
负责人：
Kexin Xu
金额：
$ 12.57万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700823
关键词：
Affinity Chromatography Androgen Receptor Androgens Binding Biological Biological Assay Biological Process Caring Catalytic Domain Cell model Cell physiology Clinical Combined Modality Therapy Complex Data Development Dimensions Drug Targeting Elements Epigenetic Process Foundations Gene Activation Gene Silencing Genes Genetic Transcription Goals Growth Health Histone H3 In Vitro Learning Light Link Lymphoma Lysine Malignant neoplasm of prostate Mass Spectrum Analysis Mentors Methylation Methyltransferase Modeling Molecular Mutate Oncogenic Pathway interactions Pharmaceutical Preparations Phase Polycomb Pre-Clinical Model Prostate Proteins Proteomics Receptor Signaling Regulation Research Resistance Role Signal Transduction Solid Neoplasm Staging Techniques Testing Therapeutic Transactivation Transcriptional Activation Translations Treatment Protocols Work androgen independent prostate cancer anticancer research base cancer therapy castration resistant prostate cancer clinical application clinical practice efficacy testing genetic profiling genome-wide human EZH2 protein inhibitor/antagonist mutant novel pre-clinical programs prostate cancer cell prostate cancer model research study tool transcription factor transcriptome sequencing tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Castration resistant prostate cancer (CRPC) remains a major clinical challenge, as tumors at this stage are largely incurable. Cumulative evidence, including ours, suggests that the methyltransferase EZH2 represents a promising drug target for CRPC treatment. Although EZH2 is best known for its role as the catalytic subunit of Polycomb repressive complex 2 (PRC2), which methylates histone H3 on lys27 for gene silencing, additional functions of EZH2 have been indicated. It is in consistence with our prior work showing a specific transactivation function of EZH2 in CRPC, which requires its enzymatic activity and the ability as a co-activator for critical transcription factors such as the androgen receptor (AR). With the identification of targeted inhibitors against EZH2 methyltransferase activity, we were able to evaluate the biological effects of pharmacological inhibition of EZH2 in CRPC cells. Indeed, EZH2 inhibitor significantly retarded the growth of prostate cancer cells. Intriguingly, the inhibitor in CRPC cells didn't up-regulate the expression of EZH2-repressed genes, but instead significantly down-regulated the levels of EZH2-activated genes. Furthermore, AR methylation was modulated by EZH2 methyltransferase activity. Meanwhile, our proteomic analysis found ?-catenin, a well-known regulator of AR signaling, as one of EZH2-interacting proteins that are not associated with other components of PRC2 complex. All these compelling data reinforce our hypothesis that EZH2 exerts a polycomb-independent function linking to the AR signaling, which is critical for CRPC development. Therefore, I proposed to set up the preclinical models to test the efficacy of EZH2 inhibitor, either alone or combined with AR antagonists, in prostate cancer (Aim 1), and investigate the transcriptional network composed of EZH2, AR as well as ¿-catenin in regulation of CRPC- related genes (Aim 2). I will further identify novel proteins that interact with EZH2 and determine its oncogenic functions (Aim 3). I am confident that our research will add an entirely new dimension to the field of cancer research, and provide a compelling foundation for the clinical practice of aggressive solid tumors.

描述（由申请人提供）：去势抵抗性前列腺癌（CRPC）仍然是一个重大的临床挑战，因为这一阶段的肿瘤基本上无法治愈。包括我们在内的累积证据表明，甲基转移酶 EZH2 代表了 EZH2 治疗的一个有前途的药物靶点。最为人所知的是其作为 Polycomb 抑制复合物 2 (PRC2) 的催化亚基的作用，该复合物可甲基化组蛋白 H3 lys27 用于基因沉默，EZH2 的其他功能已被表明，这与我们之前的工作一致，显示 EZH2 在 CRPC 中具有特定的反式激活功能，这需要其酶活性和作为关键转录因子（例如）的共激活剂的能力。通过鉴定针对 EZH2 甲基转移酶活性的靶向抑制剂，我们能够评估 EZH2 药理抑制在 CRPC 中的生物学效应。事实上，EZH2 抑制剂可以延缓前列腺癌细胞的生长，有趣的是，CRPC 细胞中的抑制剂不会上调 EZH2 抑制基因的表达，而是显着下调 EZH2 激活基因的水平。甲基化受到 EZH2 甲基转移酶活性的调节，同时，我们的蛋白质组学分析发现 β-catenin（一种众所周知的 AR 信号传导调节因子）是其中之一。与 PRC2 复合物的其他成分无关的 EZH2 相互作用蛋白所有这些令人信服的数据都强化了我们的假设，即 EZH2 发挥与 AR 信号传导相关的多梳独立功能，这对于 CRPC 的发展至关重要。临床前模型测试 EZH2 抑制剂单独或与 AR 拮抗剂联合治疗前列腺癌的疗效（目标 1），并研究由 EZH2、AR 和 AR 组成的转录网络¿ -连环蛋白对 CRPC 相关基因的调节（目标 2）我将进一步鉴定与 EZH2 相互作用的新蛋白质并确定其致癌功能（目标 3）我相信我们的研究将为该领域增添一个全新的维度。癌症研究，并为侵袭性实体瘤的临床实践提供了令人信服的基础。