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: 8303653
• 负责人: Maureen K Bunger
• 金额: $ 9.24万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303653
• 关键词: Determining; Epigenetic; Targets; Milk; Thistle

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。水飞蓟提取物（Silybum marianum L. Gaertn）已被研究作为实验性预防和治疗多种上皮癌包括前列腺癌的药物。虽然该提取物中活性化合物的精确直接或间接分子靶点尚未确定，但我们显示了初步证据，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系中EZH2蛋白的调节和活性。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甲基转移酶募集到基因启动子。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。鉴于水飞蓟宾对表观遗传事件的已知修饰因子的影响，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。本研究采用探索性全基因组方法，通过建立两部分筛选系统来揭示水飞蓟宾素的表观遗传靶点。在第一个筛选中，在没有遗传异质性的情况下显示高表达变异的等位基因是通过检查因非前列腺癌相关原因而接受前列腺切除术的无血缘关系个体的正常人类前列腺组织中的蛋白质表达来确定的。在第二个筛选中，使用前列腺肿瘤细胞系鉴定对重复剂量水飞蓟宾表现出不同反应的等位基因。正在验证的假设是，等位基因在正常组织中表现出高表达水平的异质性，这些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；也就是正常组织中最易受表观遗传调控的等位基因。通过识别这些等位基因并了解其在正常组织中的表观遗传异质性，我们进一步了解水飞蓟宾等饮食因素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水飞蓟提取物影响的亚稳态外胚层。水飞蓟提取物（Silybum marianum L. Gaertn）已被研究作为实验性预防和治疗多种上皮癌包括前列腺癌的药物。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，我们进一步了解了水飞蓟宾等膳食补充剂如何长期对前列腺组织产生影响。