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牛奶蓟衍生化合物表观遗传学调节的等位基因靶标。牛奶蓟（Silybum Marianum L. gaertn）的提取物已被研究为针对包括前列腺癌在内的各种上皮癌的实验预防和治疗剂。尽管尚未鉴定出该提取物中活性化合物的精确直接或间接分子靶标，但我们显示的初步证据表明，部分纯化的牛奶蓟提取物硅质素会影响各种前列腺肿瘤细胞衬里中蛋白EZH2的调节和活性。 EZH2是一种蛋白甲基转移酶，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。它也被认为是人类中更具侵略性前列腺和乳腺癌的生物标志物。鉴于硅酸盐素对已知的表观遗传事件修饰剂的影响，我们假设牛奶蓟的肿瘤预防特性可以通过表观遗传机制进行。拟议的工作采用探索性基因组的方法来通过开发两部分筛选系统来揭示硅酸盐素的表观遗传靶标。在第一个屏幕中，在没有遗传异质性的情况下显示出很高表达变化的等位基因是通过检查正常人前列腺组织中的蛋白质表达来确定来自前列腺切除术的非相关个体，出于非疾病癌症相关的原因。在第二个筛选中，使用前列腺肿瘤细胞系列鉴定出对硅酸盐反复给药的反应差异的等位基因。被检验的假设是等位基因在正常组织中显示出高表达水平的异质性，这也受到反复暴露于硅酸盐素的影响。又称A，最容易受到正常组织表观遗传调节的等位基因。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，我们可以提高人们对饮食因素（如硅酸盐素）如何在长期内对前列腺组织产生影响的理解。公共卫生相关性：拟议研究的总体目标是发现受牛奶蓟提取物影响的亚稳态。牛奶蓟（Silybum Marianum L. gaertn）的提取物已被研究为针对包括前列腺癌在内的各种上皮癌的实验预防和治疗剂。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，我们可以在长期内对饮食补充剂（如硅酸盐素）对前列腺组织产生影响。