Epigenetics of Tea Polyphenols in Cancer Prevention

茶多酚在癌症预防中的表观遗传学

• 批准号: 7762249
• 负责人: TRYGVE O TOLLEFSBOL
• 金额: $ 24.07万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762249
• 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; 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; chemotherapy; cytotoxic; gallocatechol; histone methyltransferase; in vivo; malignant breast neoplasm; novel strategies; polyphenol; pre-clinical; prevent; promoter; public health relevance; response; transcription factor; tumor; tumor progression; tumorigenesis

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）： 绿茶在全球范围内被广泛食用，并具有化学预防和抗癌特性。绿茶的主要组成部分是多酚，（ - ） - epigallocatechin-3-gallate（EGCG），可有效预防乳腺癌，这是美国女性与癌症相关死亡的主要原因。许多研究表明，EGCG抑制了DNA甲基转移酶1和端粒酶活性，这些活性在肿瘤发生过程中起着关键作用。 EGCG抑制端粒酶会导致癌细胞凋亡，而口服EGCG的凋亡是有效的，尤其是在表达端粒酶的癌细胞中。我们发现EGCG主要通过对端粒酶调节基因，HTERT和其他实验室的转录控制来下调端粒酶，现在已经报告了类似的发现。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的作用尚未完全了解。主要假设是绿茶多酚可以防止表观遗传过程导致乳腺癌中端粒酶激活。次要假设是，绿茶调节组蛋白脱乙酰基酶（HDACS），组蛋白甲基转移酶（HMTases）和/或DNA甲基转移酶（DNMTS）的可用性以及对HTERT促进乳腺癌预防的关键转录因子。 AIM 1将评估绿茶多酚在控制组蛋白甲基化和乙酰化中的作用，这与已知参与HTERT调控有关的关键残基。 AIM 2将评估HTERT启动子与关键表观遗传调节剂（例如HDAC，HMTase和dnmts以及HTERT的主要转录调节剂）的相互作用。目的3是使用乳腺临床前癌症预防模型来衡量绿茶多酚对控制HTERT启动子的表观遗传过程的体内影响。由于绿茶有望减少乳腺癌的发生率，因此该提案的目的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了乳腺癌的发生。目的是，这些研究的结果将有助于在预防癌症预防中更有效地使用绿茶和/或多酚，并将有助于阐明绿茶赋予其化学预防特性的机制。公共卫生相关性：癌症患者的化学疗法通常会产生不令人满意的和/或有毒作用。因此，有必要对预防癌症或治疗的无毒或更少的细胞毒性模式进行研究。拟议的研究将有助于阐明饮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，而且通过表观遗传学过程来导致预防癌症的新方法。