Determining Epigenetic Targets of Milk Thistle Extract in Prostate

确定前列腺中水飞蓟提取物的表观遗传靶点

• 批准号: 7659824
• 负责人: Maureen K Bunger
• 金额: $ 26.78万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-10 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659824
• 关键词: Affect; Age; Alleles; Biological Markers; Candidate Disease Gene; Cell Culture Techniques; Cell Death; Cell Line; Chromatin Structure; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Data; Diet; Dietary Factors; Disease Outcome; Dose; EZH2 gene; Elements; Epigenetic Process; Epithelial; Event; Exposure to; Genes; Genetic; Genetic Heterogeneity; Genetic Polymorphism; Genome; Genotype; Goals; Health; Heterogeneity; Human; Individual; Lead; Legitimacy; Life; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Medicine; Methylation; Milk Thistle; Milk thistle extract; Molecular Target; Monitor; Normal tissue morphology; Phenotype; Play; Population; Predisposition; Preventive; Property; Prostate; Prostatectomy; Prostatic Neoplasms; Protein Methyltransferases; Proteins; Proteomics; Regulation; Research; Role; Scheme; Screening procedure; Stimulus; System; Testing; Therapeutic Agents; Tissue Sample; Tissues; Tumor Cell Line; Variant; Work; base; cancer prevention; design; dietary supplements; follow-up; genetic association; genome-wide; histone methyltransferase; mRNA Expression; malignant breast neoplasm; neoplastic cell; numb protein; nutrition; promoter; protein expression; public health relevance; response; silibinin; tool; tumor

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to discover allelic targets for epigenetic regulation by milk thistle-derived compounds. Extracts of milk thistle (Silybum marianum L. Gaertn) have been investigated as experimental preventive and therapeutic agents against a variety of epithelial cancers including prostate cancer. While the precise direct or indirect molecular targets of the active compounds in this extracts have not been identified, we show preliminary evidence that the partially purified milk thistle extract silibinin affects the regulation and activity of the protein EZH2 in a variety of prostate tumor cell liners. EZH2 is a protein methyltransferase that can alter chromatin structure and lead to recruitment of DNA methyltransferases to gene promoters. It is also been characterized as a biomarker of the more aggressive prostate and breast cancers in humans. Given the effects of silibinin on a known modifier of epigenetic events, we hypothesize that the tumor preventative properties of milk thistle may proceed through epigenetic mechanisms. The proposed work takes an exploratory genome-wide approach to uncovering epigenetic targets of silibinin by developing a two part screening system. In the first screen, alleles that show high expression variation in the absence of genetic heterogeneity are determined by examining protein expression in normal human prostate tissue from unrelated individuals undergoing prostatectomies for non-prostate cancer related reasons. In the second screen, alleles that show differential response to repeated dosing of silibinin are identified using a prostate tumor cells line. The hypothesis being tested is that alleles the show high expression level heterogeneity in a normal tissue, that are also affected by repeated exposure to silibinin are metastable epialleles; a.k.a, alleles most susceptible to epigenetic regulation in normal tissue. By identifying these alleles and understanding their epigenetic heterogeneity in a normal tissue, we advance our understanding of how dietary factors such as silibinin exert their effects on prostate tissue over the long term. PUBLIC HEALTH RELEVANCE: The overall goal of the proposed research is to discover metastable epialleles that are influenced by milk thistle extracts. Extracts of milk thistle (Silybum marianum L. Gaertn) have been investigated as experimental preventive and therapeutic agents against a variety of epithelial cancers including prostate cancer. By identifying these alleles and understanding their epigenetic heterogeneity in a normal tissue, we advance our understanding of how dietary supplements such as silibinin exert their effects on prostate tissue over the long term.

描述（由申请人提供）：拟议研究的总体目标是发现水飞蓟衍生化合物的表观遗传调控等位基因靶标。水飞蓟（Silybum marianum L. Gaertn）提取物已被研究作为针对包括前列腺癌在内的多种上皮癌的实验性预防和治疗剂。虽然该提取物中活性化合物的精确直接或间接分子靶标尚未确定，但我们提供了初步证据，表明部分纯化的水飞蓟提取物水飞蓟宾影响多种前列腺肿瘤细胞衬里中蛋白质 EZH2 的调节和活性。 EZH2 是一种蛋白质甲基转移酶，可以改变染色质结构并导致 DNA 甲基转移酶招募至基因启动子。它也被认为是人类更具侵袭性的前列腺癌和乳腺癌的生物标志物。鉴于水飞蓟宾对已知的表观遗传事件调节剂的影响，我们假设水飞蓟的肿瘤预防特性可能通过表观遗传机制进行。拟议的工作采用探索性全基因组方法，通过开发两部分筛选系统来揭示水飞蓟宾的表观遗传靶标。在第一次筛选中，通过检查因非前列腺癌相关原因接受前列腺切除术的无关个体的正常人前列腺组织中的蛋白质表达，确定在不存在遗传异质性的情况下表现出高表达变异的等位基因。在第二次筛选中，使用前列腺肿瘤细胞系鉴定了对重复给药水飞蓟宾表现出差异反应的等位基因。正在测试的假设是，在正常组织中表现出高表达水平异质性的等位基因，也受到反复暴露于水飞蓟宾的影响，是亚稳态表观等位基因；又名，正常组织中最容易受到表观遗传调控的等位基因。通过识别这些等位基因并了解它们在正常组织中的表观遗传异质性，我们加深了对水飞蓟宾等饮食因素如何长期对前列腺组织产生影响的理解。公共健康相关性：拟议研究的总体目标是发现受水飞蓟提取物影响的亚稳态表观等位基因。水飞蓟（Silybum marianum L. Gaertn）提取物已被研究作为针对包括前列腺癌在内的多种上皮癌的实验性预防和治疗剂。通过识别这些等位基因并了解它们在正常组织中的表观遗传异质性，我们加深了对水飞蓟宾等膳食补充剂如何长期对前列腺组织发挥作用的理解。