Epigenetics of Dietary EGCG in Cancer Prevention

描述（由申请人提供）：膳食多酚在人类饮食中很常见，具有化学预防和抗癌活性。绿茶是全球消费最多的饮料之一，绿茶的主要成分是多酚(-)-表没食子儿茶素没食子酸酯（EGCG）。许多研究表明，EGCG具有有效的抗癌特性，但EGCG发挥这些作用的机制尚不清楚。最近的研究表明，这种膳食多酚会改变DNA甲基转移酶I的活性，从而导致甲基化控制的癌症基因表达的变化。端粒酶是参与肿瘤发生的重要基因，通过DNA甲基化控制，我们发现EGCG下调癌细胞中端粒酶催化亚基hTERT的转录导致细胞凋亡。除了DNA甲基转移酶外，组蛋白去乙酰化酶也是癌症端粒酶基因的重要表观遗传调控因子。本研究的主要假设是EGCG改变癌细胞端粒酶的表观遗传表达，导致端粒酶抑制并诱导细胞凋亡。第二种假设是，这是通过EGCG对DNA甲基转移酶和/或组蛋白去乙酰化酶的影响而发生的，这些酶会改变端粒酶基因的表达。为了验证这些假设，目的1是测量egcg处理和未处理的癌症和对照细胞中hTERT启动子的DNA甲基化和组蛋白乙酰化的变化。目的2是检测E2F-1甲基化敏感抑制因子在ecgc治疗和未治疗的癌症和对照细胞中与hTERT启动子的结合。目的3是评估裸鼠移植的egcg介导的端粒酶抑制的体内机制。本项目的目的是阐明EGCG（一种常见的膳食成分）抑制癌细胞生长的体外和体内表观遗传机制。最终，这一建议的完成可能会导致阐明膳食多酚调节其化学预防和抗癌作用的机制，从而促进绿茶和/或多酚在癌症预防和治疗中的更有效使用。

DESCRIPTION (provided by applicant): Dietary polyphenols are common in the human diet and have chemopreventive and anticancer activities. Green tea is one of the most consumed beverages worldwide and a major constituent of green tea is the polyphenol (-)-epigallocatechin gallate (EGCG). Many studies have shown that EGCG has potent anticancer properties but the mechanisms whereby EGCG imparts these effects are unknown. Recent studies have indicated that this dietary polyphenol alters the activity of DNA methyltransferase I leading to changes in the expression of methylation-controlled cancer genes. Telomerase is an important gene involved in oncoqenesis that is controlled through DNA methvlation and we have found that EGCG down-regulates transcription of hTERT (the catalytic subunit of telomerase) in cancer cells leading to apoptosis. In addition to the DNA methyltransferases, histone deacetylases are also important epigenetic regulators of the telomerase gene in cancer. The main hypothesis of this proposal is that EGCG alters the epigenetic expression of telomerase in cancer cells leading to telomerase inhibition and induction of apoptosis. A secondary hypothesis is that this occurs through the effects of EGCG on the DNA methyltransferases and/or histone deacetylases which alter telomerase gene expression. To test these hypotheses, Aim 1 is to measure changes in DNA methylation and histone acetylation of the hTERT promoter in EGCG-treated and -untreated cancer and control cells. Aim 2 is to detect the binding of the E2F-1 methylation-sensitive repressor to the hTERT promoter in ECGC-treated and -untreated cancer and control cells. Aim 3 is to evaluate the in vivo mechanisms of EGCG-mediated telomerase inhibition using xenografts implanted into nude mice. The goal of this project is to elucidate the in vitro and in vivo epigenetic mechanisms whereby EGCG, a common dietary component, causes growth inhibition of cancer cells. Ultimately, completion of this proposal may lead to elucidation of the mechanisms through which dietary polyphenols mediate their chemopreventive and anticarcinogenic effects thereby facilitating more effective uses of green tea and/or polyphenols in cancer prevention and therapy.