Targeting EZH2 in Prostate Cancer by Luteolin

通过木犀草素靶向前列腺癌中的 EZH2

• 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
• 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

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）： 本研究的总体目标是评估木犀草素在预防进展方面的功效 前列腺癌的研究并揭示其抗癌作用的分子基础。组蛋白的翻译后修饰对于染色质结构和基因表达的调节至关重要。增强子 Zeste 同源物 2 (EZH2) 是多梳抑制复合物 (PRC)-2 的催化亚基，通过催化组蛋白 H3 在赖氨酸 27 (H3K27) 上的三甲基化参与染色质重塑和基因沉默。 EZH2介导的表观遗传基因沉默在前列腺癌的发生和进展中发挥着重要作用。 EZH2 表达增加可促进上皮细胞的肿瘤转化和癌症进展。从机制上讲，EZH2介导的H3K27三甲基化导致前列腺癌中大量抑癌基因的沉默，例如CDKN2A/p16、CDH1/E-钙粘蛋白、禁用同源物2相互作用蛋白(DAB2IP)和金属蛋白酶组织抑制剂(TIMP)-3。功能分析已证明 EZH2 是一种真正的癌基因。我们的初步数据表明：i) 在前列腺癌进展过程中 EZH2 逐渐增加，以及其在癌症与相应正常/良性组织中的表达差异，ii) 在计算机研究中，植物黄酮木犀草素与 EZH2 的活性位点结合，iii) 木犀草素与 EZH2 和 H3k27me3 蛋白的相互作用 - 离体研究，iii) 木犀草素抑制 前列腺癌细胞中的 EZH2 表达和 H3K27me3，iv) 木犀草素改变转录组和 miRNA 表达，v) 木犀草素降低前列腺癌细胞的增殖和侵袭性，vi) 木犀草素诱导肿瘤抑制基因的重新表达。我们的工作假设是，木犀草素介导的 EZH2 及其组蛋白赖氨酸 N-甲基转移酶活性的抑制不仅通过组蛋白甲基化的变化，而且还通过肿瘤抑制基因启动子的表观遗传修饰和 EZH2 调节 miRNA 水平的翻译后变化来抑制前列腺癌的进展。我们提出了四个互补的具体目标来确定：(1) 木犀草素对 EZH2 和其他 PRC2 复合蛋白的影响，(2) 木犀草素逆转 EZH2 介导的表观遗传基因沉默的能力，(3) 木犀草素对影响前列腺癌细胞中 EZH2 介导的变化的特定 miRNA 的调节作用，以及 (4) 木犀草素介导的作用 使用小鼠前列腺转基因腺癌 (TRAMP) 模型对相关体内情况进行 EZH2 抑制和相关分子机制，该模型再现了人类疾病。前列腺癌非常普遍，是美国男性癌症相关死亡的第二大原因。完成这些研究所产生的知识有可能为退伍军人管理局医疗保健系统提供独特的机会，为被诊断患有低级别、小体积前列腺癌的退伍军人管理局男性制定有效的治疗策略。当前的现实需要这种新颖的策略，即不同患者中组织学相同的癌症可能表现出广泛不同的生物学行为，并且前列腺癌患者比一般人群更有可能患有显着的合并症。总之，我们将定义 1) 的角色 EZH2 介导的表观遗传重编程在驱动前列腺癌进展中的作用，因为 EZH2-H3K27me3 表观遗传途径似乎对于抑癌基因的抑制非常重要，2) 木犀草素的有益作用，这将为接受主动监测或有生化复发风险的前列腺癌患者的治疗树立新的范例。