Epigenetics of Tea Polyphenols in Cancer Prevention

茶多酚在癌症预防中的表观遗传学

基本信息

批准号：
8015363
负责人：
TRYGVE O TOLLEFSBOL
金额：
$ 23.35万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8015363
关键词：
Acetylation Affect Apoptosis Attention Azacitidine Beverages Binding Biological Models Breast Breast Cancer Cell Breast Cancer Prevention Cancer Control Cancer Etiology Cancer Patient Cells Cessation of life Chemopreventive Agent Chromosomes DNA Methylation DNA Methyltransferase DNA Modification Methylases Dietary Component Dietary Factors Down-Regulation E2F1 gene Enzymes Epigallocatechin Gallate Epigenetic Process Female Gene Expression Gene Expression Regulation Goals Green tea Health Histone Acetylation Histone Deacetylase Inhibitor Histone Deacetylation Histones In Vitro Incidence Investigation Laboratories Lead Malignant Neoplasms Measures Mediating Methylation Modeling Oral Oral Administration Outcome Study Pathway interactions Play Prevention therapy Process Property RNA Interference Regulation Regulator Genes Reporting Role TERT gene Tea Techniques Telomerase Telomerase inhibition Toxic effect Transcriptional Regulation Trichostatin A United States Work breast tumorigenesis cancer cell cancer prevention cancer therapy chemotherapy cytotoxic gallocatechol histone methyltransferase in vivo malignant breast neoplasm novel strategies polyphenol pre-clinical prevent promoter response transcription factor tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Green tea is widely consumed as a popular beverage worldwide and has chemopreventive and anticancer properties. A major constituent of green tea is the polyphenol, (-)-epigallocatechin-3-gallate (EGCG), that is effective in the prevention of breast cancer, a leading cause of cancer-related deaths among females in the United States. Many studies have indicated that EGCG inhibits DNA methyltransferase 1 and telomerase activity which play critical roles in the progression of tumorigenesis. Telomerase inhibition by EGCG leads to apoptosis of cancer cells and oral administration of EGCG is effective especially in telomerase-expressing cancer cells. We discovered that EGCG down-regulates telomerase primarily through transcriptional control of the telomerase regulatory gene, hTERT, and other laboratories have now reported similar findings. Alterations of the hTERT gene by green tea polyphenols involve changes in histone acetylation, DNA methylation, and transcription factor binding although the roles of other epigenetic processes and the in vivo mechanisms are not fully understood. The main hypothesis is that green tea polyphenols prevent the epigenetic processes that lead to telomerase activation in breast cancer. A secondary hypothesis is that green tea modulates the availability of the histone deacetylases (HDACs), histone methyltransferases (HMTases) and/or DNA methyltransferases (DNMTs) as well as key transcription factors to the hTERT promoter leading to breast cancer prevention. Aim 1 will assess the role of green tea polyphenols in controlling histone methylation and acetylation at key residues known to be involved in hTERT regulation. Aim 2 will evaluate the interactions of the hTERT promoter with key epigenetic modulators such as the HDACs, HMTases and DNMTs as well as major transcriptional regulators of hTERT. Aim 3 is to measure the in vivo effects of green tea polyphenols on epigenetic processes controlling the hTERT promoter using breast preclinical cancer prevention models. Since green tea has promise in reducing the incidence of breast cancer, the goal of this proposal is to determine the epigenetic mechanisms, both in vitro and in vivo, whereby this common dietary component decreases the incidence of breast cancer. It is intended that the outcome of these studies will facilitate more effective uses of green tea and/or polyphenols in cancer prevention and will help elucidate the mechanisms through which green tea imparts its chemopreventive properties. PUBLIC HEALTH RELEVANCE : Chemotherapy of cancer patients often produces unsatisfactory and/or toxic effects. Investigations into non-toxic or less cytotoxic modes of cancer prevention or treatment are therefore warranted. The proposed studies will help elucidate how dietary green tea imparts its chemopreventive and anticancer effects and may lead to novel approaches to cancer prevention through control not only of dietary factors, but also through epigenetic processes.

描述（由申请人提供）：绿茶作为一种流行饮料在世界范围内被广泛消费，并具有化学预防和抗癌特性。绿茶的主要成分是多酚，(-)-表没食子儿茶素-3-没食子酸酯 (EGCG)，它可以有效预防乳腺癌，乳腺癌是美国女性癌症相关死亡的主要原因。许多研究表明，EGCG 抑制 DNA 甲基转移酶 1 和端粒酶活性，这些酶在肿瘤发生的过程中发挥着关键作用。 EGCG抑制端粒酶导致癌细胞凋亡，口服EGCG对表达端粒酶的癌细胞尤其有效。我们发现 EGCG 主要通过端粒酶调节基因 hTERT 的转录控制来下调端粒酶，其他实验室现在也报告了类似的发现。绿茶多酚对 hTERT 基因的改变涉及组蛋白乙酰化、DNA 甲基化和转录因子结合的变化，尽管其他表观遗传过程的作用和体内机制尚未完全了解。主要假设是绿茶多酚可以阻止导致乳腺癌端粒酶激活的表观遗传过程。第二个假设是绿茶调节组蛋白脱乙酰酶 (HDAC)、组蛋白甲基转移酶 (HMTase) 和/或 DNA 甲基转移酶 (DNMT) 以及 hTERT 启动子的关键转录因子的可用性，从而预防乳腺癌。目标 1 将评估绿茶多酚在控制已知参与 hTERT 调节的关键残基上的组蛋白甲基化和乙酰化中的作用。目标 2 将评估 hTERT 启动子与关键表观遗传调节剂（如 HDAC、HMTase 和 DNMT）以及 hTERT 主要转录调节剂的相互作用。目标 3 是使用乳腺癌临床前癌症预防模型来测量绿茶多酚对控制 hTERT 启动子的表观遗传过程的体内影响。由于绿茶有望降低乳腺癌的发病率，因此该提案的目标是确定体外和体内的表观遗传机制，从而使这种常见的饮食成分降低乳腺癌的发病率。这些研究的结果将有助于更有效地使用绿茶和/或多酚来预防癌症，并有助于阐明绿茶赋予其化学预防特性的机制。公众健康相关性：癌症患者的化疗常常产生令人不满意的和/或毒性作用。因此，有必要研究无毒或细胞毒性较小的癌症预防或治疗模式。拟议的研究将有助于阐明膳食绿茶如何赋予其化学预防和抗癌作用，并可能通过控制饮食因素以及通过表观遗传过程找到预防癌症的新方法。