Epigenetics of Tea Polyphenols in Cancer Prevention

描述（由申请人提供）： 绿色茶作为一种受欢迎的饮料在世界范围内被广泛消费，并且具有化学预防和抗癌特性。绿色茶的主要成分是多酚，（-）-表没食子儿茶素-3-没食子酸酯（EGCG），其有效预防乳腺癌，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，在肿瘤的发生发展中起重要作用。通过EGCG抑制端粒酶导致癌细胞凋亡，并且口服给予EGCG特别是在表达端粒酶的癌细胞中有效。我们发现EGCG主要通过转录控制端粒酶调节基因hTERT来下调端粒酶，其他实验室现在也报道了类似的发现。绿色茶多酚对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。主要的假设是，绿色茶多酚阻止了导致乳腺癌端粒酶激活的表观遗传过程。第二个假设是，绿色茶调节组蛋白脱乙酰基酶（HDAC）、组蛋白甲基转移酶（HMT酶）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，从而导致乳腺癌预防。目的1将评估绿色茶多酚在控制组蛋白甲基化和乙酰化中的作用，这些甲基化和乙酰化是已知参与hTERT调控的关键残基。目的2将评估hTERT启动子与关键的表观遗传调节因子如HDAC、HMT酶和DNMT以及hTERT的主要转录调节因子的相互作用。目的3是使用乳腺癌临床前预防模型测量绿色茶多酚对控制hTERT启动子的表观遗传过程的体内作用。由于绿色茶有希望降低乳腺癌的发病率，本提案的目标是确定体外和体内的表观遗传机制，从而这种常见的饮食成分降低乳腺癌的发病率。这些研究的结果将促进绿色茶和/或多酚在癌症预防中的更有效的用途，并将有助于阐明绿色茶赋予其化学预防特性的机制。公共卫生相关性：癌症患者的化疗通常会产生令人不满意的和/或毒性作用。因此，有必要对无毒或细胞毒性较小的癌症预防或治疗模式进行调查。拟议的研究将有助于阐明饮食绿色茶如何赋予其化学预防和抗癌作用，并可能导致新的方法来预防癌症，不仅通过控制饮食因素，而且通过表观遗传过程。

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.