Regulation of Polycomb Repressive Complex 1 by EZH2 Regulated microRNAs in Cancer

EZH2 调节的 microRNA 在癌症中对 Polycomb 抑制复合物 1 的调节

基本信息

批准号：
8997389
负责人：
Sooryanarayana Varambally
金额：
$ 30.5万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-22 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997389
关键词：
BMI1 gene Biological Biological Markers Cancer Cell Growth Cancer Etiology Cell Adhesion Molecules Cell Line Cell Survival Cell physiology Cells Cessation of life Code Complex Data Development Diagnostic Disease Disease Outcome Disease Progression Down-Regulation E-Cadherin EZH2 gene Early Diagnosis Epigenetic Process Etiology Event Failure Family Gene Expression Gene Silencing Genes Genomics Goals Health Histone H3 Histones In Vitro Investigation Link Lysine Malignant Neoplasms Malignant neoplasm of prostate MicroRNAs Molecular Monitor Mutation Oncogenic PRC1 Protein Pathway interactions Patients Play Polycomb Prognostic Marker Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins Public Health RNA Regulation Replacement Therapy Role Sampling Small RNA Testing Therapeutic Tissues Transcription Repressor/Corepressor Tumor Suppressor Proteins Tumor Tissue United States Work advanced disease anticancer research cancer cell cancer diagnosis cancer initiation cancer therapy cell type clinically significant cohort disease diagnosis gene repression histone methyltransferase improved in vivo in vivo Model insight malignant breast neoplasm member men overexpression prostate cancer cell prostate carcinogenesis therapeutic target tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the second most common cause of cancer-related death in men in the United States. While multiple molecular events contribute to prostate cancer progression, it has become increasingly evident that epigenetic changes play pivotal roles in regulating cancer development. Polycomb repressive complex (PRC) members maintain the gene expression status of a cell by epigenetically modifying histone proteins. Histone methyltransferase EZH2, an oncogenic PRC2 member, initiates the transcriptional repression by trimethylating histone H3 at lysine 27. We have shown that EZH2 is overexpressed in aggressive prostate and breast cancers, predicts disease outcome, and is required for cancer cell survival. In addition, our studies have shown that EZH2 down-regulates multiple tumor suppressors and a genomic loss of microRNA-101 results in unregulated expression of EZH2 in aggressive tumors. While the role of EZH2 in regulating protein-coding genes is known, its role in regulating microRNA (miR) expression has not been studied. MiRs are critical regulators of cellular functions and are commonly altered in cancers including down regulation of several tumor suppressor miRs. Thus, we hypothesize that transcriptional repressor EZH2 plays a key role in regulating microRNA expression by epigenetic silencing and EZH2-regulated miRs play critical roles in PCa progression. Our preliminary data suggest that EZH2 down regulates multiple miRs, including miR-203 and the miR-200a, miR-200bc family. MiR-203 and mir-200a, bc in turn regulate PRC1 members, BMI1 and RING2. Thus the aims of this proposal are to extend these findings and gain further insights into the regulation of miRs by EZH2 and the role of these miRs in PCa development. In order to accomplish these goals, in Specific Aim 1, we will investigate the role of EZH2 in regulating miR expression in multiple cell types. We will first perform miR profiling using RNA from prostate cell lines in which EZH2 expression is modulated. We will validate the EZH2 regulated miR expression in prostate tumor tissues and correlate them with EZH2 expression. In Specific Aim 2, we will investigate the role of EZH2-regulated miRs in PCa and their role in targeting the PRC1 members. In Specific Aim 3, we will investigate the role of EZH2-regulated miRs in prostate tumorigenesis. We will use select EZH2-regulated miRs that are directly repressed by EZH2 and characterize the consequences of their modulation using both cell line and in vivo models of PCa. Relevance to Public Health: Successful completion of the proposed work will provide evidence for an intricate network of miR and epigenetic regulators in PCa development and identify potential diagnostic and prognostic markers, which in turn may improve PCa therapy through better diagnosis and disease monitoring. Our results may ultimately provide credence for therapeutic "re-introduction" of EZH2-repressed tumor suppressor miRs in cancer.

描述（由申请人提供）：前列腺癌（PCA）是美国男性与癌症相关死亡的第二大原因。尽管多个分子事件有助于前列腺癌的进展，但越来越明显的是表观遗传变化在调节癌症发展中起关键作用。 Polycomb抑制复合物（PRC）成员通过表观遗传修饰组蛋白蛋白质维持细胞的基因表达状态。组织甲基转移酶EZH2是一种致癌PRC2成员，通过赖氨酸27的三甲基化组蛋白H3启动转录抑制。我们表明，EZH2在侵袭性前列腺和乳腺癌中过表达，预测疾病的结果，并且需要用于癌细胞的存活。此外，我们的研究表明，EZH2降低了多种肿瘤抑制因子，MicroRNA-101的基因组丧失导致侵袭性肿瘤中EZH2表达不受调节。尽管已知EZH2在调节蛋白质编码基因中的作用，但尚未研究其在调节microRNA（MIR）表达中的作用。 miR是细胞功能的关键调节剂，通常在癌症中会改变，包括减少几种肿瘤抑制器miR。因此，我们假设转录阻遏物EZH2在通过表观遗传沉默和EZH2调节的MIRS调节microRNA表达中起关键作用，在PCA进程中起关键作用。我们的初步数据表明，EZH2降低了多个miR，包括miR-203和miR-200a，miR-200B00BC家族。 MiR-203和MiR-200a，BC反过来调节PRC1成员BMI1和RING2。因此，该提案的目的是扩展这些发现，并进一步了解EZH2对MIR的调节以及这些MIR在PCA开发中的作用。为了实现这些目标，在特定的目标1中，我们将研究EZH2在调节多种细胞类型中MIR表达中的作用。我们将使用来自前列腺细胞系的RNA进行MIR分析，其中调节EZH2表达。我们将验证EZH2在前列腺肿瘤组织中调节的MIR表达，并将其与EZH2表达相关。在特定的目标2中，我们将研究EZH2调节的MIR在PCA中的作用及其在靶向PRC1成员中的作用。在特定的目标3中，我们将研究EZH2调节的miR在前列腺肿瘤发生中的作用。我们将使用精选的EZH2调节的MIR，这些miR被EZH2直接抑制，并使用PCA的细胞系和体内模型来表征其调制的后果。与公共卫生的相关性：成功完成拟议的工作将为PCA开发中的MIR和表观遗传调节剂网络提供证据，并确定潜在的诊断和预后标记，这反过来又可以通过更好的诊断和疾病监测来改善PCA治疗。我们的结果最终可能会为癌症中EZH2抑制肿瘤抑制器的治疗性“重新介绍”提供信誉。