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: 7835564
• 负责人: Maureen K Bunger
• 金额: $ 13.67万
• 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 2011-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835564
• 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表观遗传调控的等位基因靶点。以水飞蓟（Silybum marianum L.）Gaertn）作为针对包括前列腺癌在内的多种上皮癌的实验性预防剂和治疗剂进行了研究。虽然在这种提取物中的活性化合物的精确的直接或间接的分子靶点尚未确定，我们显示了初步的证据表明，部分纯化的水飞蓟提取物水飞蓟宾影响各种前列腺肿瘤细胞系中的蛋白质EZH 2的调节和活性。EZH 2是一种蛋白质甲基转移酶，可以改变染色质结构并导致DNA甲基转移酶募集到基因启动子。它也被描述为人类中更具侵袭性的前列腺癌和乳腺癌的生物标志物。鉴于水飞蓟宾对表观遗传事件的已知修饰剂的影响，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。拟议的工作采取了探索性的全基因组方法，通过开发一个两部分筛选系统来揭示水飞蓟宾的表观遗传靶点。在第一次筛选中，通过检查来自因非前列腺癌相关原因而经历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来确定在不存在遗传异质性的情况下显示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对水飞蓟宾的重复给药显示差异响应的等位基因。所测试的假设是，在正常组织中显示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;也称为，在正常组织中对表观遗传调节最敏感的等位基因。通过鉴定这些等位基因并了解其在正常组织中的表观遗传异质性，我们进一步了解了膳食因素如水飞蓟宾如何长期对前列腺组织产生影响。公共卫生相关性：拟议研究的总体目标是发现受奶蓟提取物影响的亚稳定表观等位基因。以水飞蓟（Silybum marianum L.）Gaertn）作为针对包括前列腺癌在内的多种上皮癌的实验性预防剂和治疗剂进行了研究。通过鉴定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，我们进一步了解了膳食补充剂如水飞蓟宾如何长期对前列腺组织产生影响。