Targeting EZH2 in Prostate Cancer by Luteolin

通过木犀草素靶向前列腺癌中的 EZH2

基本信息

批准号：
8816655
负责人：
SANJAY GUPTA
金额：
--
依托单位：
LOUIS STOKES CLEVELAND VA MEDICAL CENTER
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：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8816655
关键词：
Acetylation Active Sites Affect American Apoptosis Automobile Driving Behavior Benign Binding Biochemical Biological Assay Biological Markers CDH1 gene CDKN2A gene Cancer Etiology Cancer Patient Catalysis Catalytic Domain Cessation of life ChIP-seq Chromatin Chromatin Structure Clinical Clinical Trials Comorbidity Complex Computer Simulation Core Biopsy DNA Binding Data Development Diagnosis Disabled Homolog 2 Protein Distant Docking Documentation E-Cadherin Edible Plants Epigenetic Process Epithelial Cells Evaluation Exhibits Flavones Gene Expression Gene Expression Profile Gene Silencing Gene Targeting General Population Genes Gleason Grade for Prostate Cancer Healthcare Systems Histologic Histone H3 Histone-Lysine N-Methyltransferase Histones Histopathologic Grade Human Inhibitory Concentration 50 Intake Knowledge Luciferases Luteolin Lysine Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Maps Measures Mediating Methionine Methylation MicroRNAs Modeling Modification Molecular Monitor Mus Neoplasm Metastasis Neoplastic Cell Transformation Oncogenes Painless Pathway interactions Patient Monitoring Patients Performance Plants Plasma Play Polycomb Post-Translational Protein Processing Preventive Process Proliferation Marker Property Prostate Prostatic Neoplasms Proteins Protocols documentation Publishing Recurrence Regulation Reporter Repression Research Research Design Research Project Grants Risk Role Site Supplementation TIMP3 gene Testing Therapeutic Agents Time Tissue Inhibitor of Metalloproteinase-3 Tissues Tumor Suppressor Genes Tumor Tissue United States Variant Work base cancer diagnosis cancer initiation chromatin remodeling dietary supplements differential expression effective therapy epigenome experience histone methylation histone methyltransferase human EZH2 protein human disease in vivo men mutant novel strategies prevent promoter prostate cancer cell prostate carcinogenesis protein complex public health relevance research study response success text searching therapeutic target transcription factor transgene expression transgenic adenocarcinoma of mouse prostate treatment strategy tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this study is to assess the efficacy of luteolin in preventing progression of prostate cancer and to uncover the molecular basis of its anticancer effects. Post-translational modification of histones is critical for regulation of chromatin structure and gene expression. Enhancer of Zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex (PRC)-2, which is involved in chromatin remodeling and gene silencing through its catalysis of the trimethylation of histone H3 on lysine 27 (H3K27). EZH2- mediated epigenetic gene silencing plays an important role in prostate cancer initiation and progression. Increased EZH2 expression promotes neoplastic transformation of epithelial cells and cancer progression. Mechanistically, EZH2-mediated trimethylation of H3K27 results in silencing of a large number of tumor suppressor genes such as CDKN2A/p16, CDH1/E-cadherin, Disabled homolog 2-interacting protein (DAB2IP) and tissue inhibitor of metalloproteinases (TIMP)-3 in prostate cancer. Functional assays have demonstrated EZH2 to be a bonafide oncogene. Our preliminary data suggest that: i) progressive increase in EZH2 during prostate cancer progression and its differential expression in cancer vs. corresponding normal/benign tissue, ii) from in silico studies, the plant flavone luteolin binds to the active site of EZH2, iii) interactin of luteolin with EZH2 and H3k27me3 proteins-ex vivo studies, iii) luteolin inhibits EZH2 expression and H3K27me3 in prostate cancer cells, iv) luteolin alters transcriptome and miRNA expression, v) luteolin decreases proliferation and invasiveness of prostate cancer cells, and vi) luteolin induces re-expression of tumor suppressor genes. Our working hypothesis is that luteolin-mediated suppression of EZH2 and its histone-lysine N- methyltransferase activity inhibits progression of prostate cancer not only through changes in histone methylation, but also through epigenetic modifications in the promoters of tumor suppressor genes and post-translational changes in the levels of EZH2-regulatory miRNAs. We propose four complementary specific aims to determine: (1) the effects of luteolin on EZH2 and other PRC2 complex proteins, (2) the ability of luteolin to reverse EZH2-mediated epigenetic gene silencing, (3) the effects of luteolin on the regulation of specific miRNAs affecting EZH2-mediated changes in prostate cancer cells, and (4) the effects of luteolin-mediated EZH2 inhibition and associated molecular mechanisms on relevant in vivo situations using the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, which recapitulate human disease. Prostate cancer is highly prevalent and the second leading cause of cancer-related deaths in men in the United States. The knowledge generated by completion of these studies has the potential to provide the VA healthcare system with unique opportunities for effective treatment strategies for VA men diagnosed with low- grade, low-volume prostate cancer. Such novel strategies are necessitated by the current realities that histologically identical cancers in different patients cn exhibit widely variant biologic behavior, and prostate cancer patients are more likely to have significant comorbidities than the general population. In conclusion, we will define the 1) role of EZH2-mediated epigenetic reprogramming in driving prostate cancer progression, as the EZH2-H3K27me3 epigenetic pathway appears to be very important for repression of tumor suppressor genes, and 2) the beneficial effects of luteolin, which will set a new paradigm in the management of prostate cancer patients undergoing active surveillance or at risk for biochemical recurrence.

描述（由申请人提供）：这项研究的总体目的是评估叶黄素在预防进展方面的功效前列腺癌并发现其抗癌作用的分子基础。组蛋白的翻译后修饰对于调节染色质结构和基因表达至关重要。 Zeste同源物2（EZH2）的增强子是PolyComb抑制复合物（PRC）-2的催化亚基，该亚基与染色质重塑和基因沉默有关，其通过对赖氨酸27（H3K27）上组蛋白H3的三甲基化的催化（H3K27）。 EZH2-介导的表观遗传基因沉默在前列腺癌的启动和进展中起重要作用。 EZH2表达增加会促进上皮细胞和癌症进展的肿瘤转化。从机械上讲，EZH2介导的H3K27的三甲基化导致大量肿瘤抑制基因的沉默，例如CDKN2A/P16，CDH1/E-Cadherin，disables Disabille同源2相互作用蛋白（DAB2IP）和金属蛋白酶（timppaiss）（timp）（Timproteinase）的疾病（Timproteinase） - 3次癌症。功能测定已证明EZH2是真正的癌基因。我们的初步数据表明：i）前列腺癌进展过程中EZH2的逐渐增加及其在癌症中的差异表达与相应的正常/良性组织，ii）ii）在硅研究中，植物黄酮叶酸酮与EZH2的活性位点结合EZH2，III，III），III）与ezh2和H3K27Me3 prote in II II I II III相互作用，II）II-Exc viv viv viv viv viv viv viv。 EZH2表达和H3K27ME3在前列腺癌细胞中，iv）lueseolin改变了转录组和miRNA表达，v）叶黄素蛋白降低了前列腺癌细胞的增殖和侵入性，而vi）叶黄素蛋白诱导了肿瘤抑制基因的重新表达。我们的工作假设是，叶黄素介导的EZH2及其组蛋白 - 溶苷N-甲基转移酶活性的活性不仅通过组蛋白甲基化的变化来抑制前列腺癌的进展，而且还通过在肿瘤抑制基因的促进剂中的表观遗传修饰而抑制了EZH2-2-抑制剂基因的启动子的表观遗传修饰。 We propose four complementary specific aims to determine: (1) the effects of luteolin on EZH2 and other PRC2 complex proteins, (2) the ability of luteolin to reverse EZH2-mediated epigenetic gene silencing, (3) the effects of luteolin on the regulation of specific miRNAs affecting EZH2-mediated changes in prostate cancer cells, and (4) the effects of luteolin-mediated EZH2抑制和相关的分子机制对相关体内情况的相关分子机制，使用小鼠前列腺（Tramp）模型的转基因腺癌（概括了人类疾病）。前列腺癌高度普遍，是美国男性与癌症相关死亡的第二大原因。通过完成这些研究而产生的知识有可能为VA医疗保健系统提供独特的机会，为诊断出患有低级，低量前列腺癌的VA男子有效治疗策略。当前的现实是，这种新型策略是必要的，即不同患者的组织学相同的癌症表现出广泛的生物学行为，而前列腺癌患者比一般人群更有可能具有明显的合并症。总之，我们将定义1） EZH2介导的表观遗传重编程在驱动前列腺癌的进展中，因为EZH2-H3K27ME3表观遗传途径对于抑制肿瘤抑制基因而言，以及2）Luteolin的有益作用非常重要，2）luteolin的有益作用，这将在现有危险中为癌症患者提供新的范围，从而为预防危险而建立新的范式。