Reversal of hypermethylation and reactivation of genes by dietary polyphenolic compounds.
Reversal of hypermethylation and reactivation of genes by dietary polyphenolic compounds.
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DOI：
10.1111/j.1753-4887.2008.00059.x
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发表时间：
2008-08
影响因子：
6.1
通讯作者：
Huang TH
中科院分区：
文献类型：
--
作者：
Yang CS;Fang M;Lambert JD;Yan P;Huang TH
Dietary polyphenolic compounds have been reported to have many interesting biological activities, including the induction of epigenetic changes and cancer prevention. In searching for the mechanisms of the anti-cancer action of (–)–epigallocatechin-3-gallate (EGCG), the major polyphenolic compound in green tea, we observed the inhibition of DNA methyltransferase (DNMT) activity by EGCG. 1 Treatment of cancer cells with EGCG caused the demethylation of the CpG islands in the promoter regions and the reactivation of methylation-silenced genes such as p16INK4a, retinoic acid receptor-ß (RAR-ß), O6-methylguanine methyltransferase (MGMT), human mutL homolog 1, and glutathione S-transferase-p. These activities have been observed in human esophageal, colon, prostate, or mammary cancer cell lines. 2 With nuclear extracts from KYSE 510 human esophageal cancer cells as the source of DNMT and poly (dI-dC) poly (dI-dC) as the substrate, EGCG was found to be a competitive inhibitor of DNMT with a Ki of 4.8 µM. 2 EGCG structural analogs from green tea,(–)–epicatechin-3-gallate (ECG),(–)–epigallocatechin (EGC), and (–)–epicatechin (EC), as well as EGCG metabolites 4′-methyl EGCG (MeEGCG) and 4′, 4 ″-dimethyl EGCG (DiMeEGCG), all inhibited DNMT dose dependently. Their activities were lower, following the order EGCG> ECG, MeEGCG> EGC, DiMeEGCG> EC. Molecular modeling of the interaction between EGCG and DNMT revealed a substantial interactive region with hemimethylated DNA and a cytosine-active pocket for subsequent methylation. Docking of EGCG into this pocket indicated that the gallate moiety (D-ring) was oriented at approximately the same position as the pyrimidyl ring of cytosine in the structural model of DNMT1, with possible hydrogen bond formation with Glu1265 and Pro1223. In addition, possible hydrogen bond formation between the hydroxyl groups of the EGCG A and B rings with Ser1229 and Cys1225, respectively, may also have contributed to the high-affinity binding. This model can also explain the lower inhibitory activities of EGCG analogs and metabolites. The inhibition of DNMT and reversal of hypermethylation by EGCG and related compounds were also observed by Lee etal. 3, 4 They observed that EGCG directly inhibited DNMT activity and partially reversed RAR-ß methylation status. Other catechol polyphenols inhibited DNMT indirectly by being methylated and converting S-adenosyl-L-methionine (SAM) to S-adenosly-L-homocysteine (SAH), which is a strong inhibitor of DNMT. Caffeic acid and chlorogenic acid also partially inhibited methylation of the promoter region of the RAR-ß gene in breast cancer cell lines. 4 However, the effect of EGCG may be gene specific or cell line specific and was not as robust as 5-aza-2′-deoxycytidine (DAC). 5 Significant demethylation and reactivation of several genes by EGCG were not observed by Chuang etal. 5 and Stresemann etal. 6 Mittal et al. 7 reported that topical applications of EGCG to the mouse skin inhibited UVB-induced global DNA hypomethylation. Because global DNA hypomethylation has been reported to be associated with hypermethylation and inactivation of specific genes during carcinogenesis, this observation is not necessarily contradictory to the concept that EGCG can prevent or reverse the hypermethylation of certain specific genes.
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影响因子：
3.6
作者：
Lee, WJ;Shim, JY;Zhu, BT
通讯作者：
Zhu, BT
影响因子：
4.2
作者：
Fang, Mingzhu;Chen, Dapeng;Yang, Chung S.
通讯作者：
Yang, Chung S.
影响因子：
4.7
作者：
Lee, WJ;Zhu, BT
通讯作者：
Zhu, BT
影响因子：
11.5
作者：
Fang, MZ;Chen, DP;Yang, CS
通讯作者：
Yang, CS
影响因子：
11.2
作者：
Stresemann, C;Brueckner, B;Lyko, F
通讯作者：
Lyko, F