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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：
8445145
负责人：
Sooryanarayana Varambally
金额：
$ 30.33万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445145
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 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 public health relevance 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(申请人提供)：前列腺癌(PCA)是美国男性癌症相关死亡的第二大常见原因。虽然多个分子事件促进了前列腺癌的进展，但越来越明显的是，表观遗传变化在调节癌症发展方面发挥了关键作用。多梳抑制复合体(PRC)成员通过对组蛋白进行表观遗传修饰来维持细胞的基因表达状态。组蛋白甲基转移酶EZH2是一个致癌的PRC2成员，它通过组蛋白H3在赖氨酸27上的三甲基化来启动转录抑制。我们已经证明，EZH2在侵袭性前列腺癌和乳腺癌中过度表达，预测疾病结果，是癌细胞生存所必需的。此外，我们的研究表明，EZH2下调了多种肿瘤抑制因子的表达，而microRNA-101的基因组缺失导致了EZH2在侵袭性肿瘤中的表达不受调控。虽然EZH2在调节蛋白质编码基因中的作用是已知的，但它在调节microRNA(MiR)表达中的作用尚未被研究。MIR是细胞功能的关键调节因子，在癌症中经常发生改变，包括几种肿瘤抑制因子MIR的下调。因此，我们假设转录抑制因子EZH2通过表观遗传沉默在调节microRNA表达中起关键作用，而EZH2调控的miRs在前列腺癌的进展中起关键作用。我们的初步数据表明，EZH2下调了多个miR，包括miR-203和miR-200a、miR-200bc家族。MIR-203和mir-200A、BC依次调控PRC1成员BMI1和RING2。因此，这项提案的目的是扩大这些发现，并进一步深入了解EZH2对MIR的监管以及这些MIR在PCA发展中的作用。为了实现这些目标，在特定的目标1中，我们将研究EZH2在多种细胞类型中调节miR表达的作用。我们将首先使用EZH2表达受调控的前列腺细胞系的RNA来进行miR谱分析。我们将验证EZH2调控的miR在前列腺癌组织中的表达，并将其与EZH2的表达相关联。在特定的目标2中，我们将研究EZH2调控的miRs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miRs在前列腺癌发生中的作用。我们将使用EZH2直接抑制的受EZH2调控的miRs，并使用细胞系和体内的PCa模型来表征它们调控的后果。与公共卫生的相关性：拟议工作的成功完成将为在PCA发展中建立一个错综复杂的miR和表观遗传调控网络提供证据，并确定潜在的诊断和预后标记物，这反过来可能通过更好的诊断和疾病监测来改进PCA治疗。我们的结果可能最终为EZH2抑制的肿瘤抑制基因miRs在癌症中的治疗“重新引入”提供证据。