Epigenetics of Tea Polyphenols in Cancer Prevention

描述(由申请人提供)： 绿茶作为一种广受欢迎的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，(-)-表没食子儿茶素没食子酸酯(EGCG)，它对预防乳腺癌有效，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，而端粒酶活性在肿瘤的发生发展中起着关键作用。EGCG抑制端粒酶活性可导致肿瘤细胞的凋亡，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的转录控制下调端粒酶，其他实验室现在也报道了类似的发现。绿茶多酚对hTERT基因的改变包括组蛋白乙酰化、DNA甲基化和转录因子结合的改变，尽管其他表观遗传过程的作用和体内机制尚不完全清楚。主要的假设是绿茶多酚阻止了导致乳腺癌端粒酶激活的表观遗传过程。第二个假设是绿茶调节组蛋白脱乙酰酶(HDACs)、组蛋白甲基转移酶(HMTase)和/或DNA甲基转移酶(Dnmts)以及hTERT启动子的关键转录因子的可用性，从而预防乳腺癌。目的1将评估绿茶多酚在控制组蛋白甲基化和关键残基乙酰化方面的作用，已知的关键残基参与hTERT调节。目的研究hTERT启动子与hTERT的主要转录调控因子，如hDACs、hMTase、Dnmts等表观遗传调控因子的相互作用。目的3利用乳腺癌临床前预防模型，研究绿茶多酚对控制hTERT启动子的表观遗传过程的体内效应。由于绿茶在降低乳腺癌发病率方面有希望，这项建议的目标是确定体外和体内的表观遗传学机制，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利用绿茶和/或多酚来预防癌症，并有助于阐明绿茶具有化学预防作用的机制。公共卫生相关性：癌症患者的化疗常常产生令人不满意的和/或毒副作用。因此，有必要研究无毒或细胞毒性较低的癌症预防或治疗模式。拟议的研究将有助于阐明饮食绿茶如何发挥其化学预防和抗癌作用，并可能不仅通过控制饮食因素，而且通过表观遗传过程，带来预防癌症的新方法。

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.