Reversal of hypermethylation and reactivation of p16INK4a RARβ, and MGMT genes by genistein and other isoflavones from soy
Reversal of hypermethylation and reactivation of p16INK4a RARβ, and MGMT genes by genistein and other isoflavones from soy
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DOI：
10.1158/1078-0432.ccr-05-0406
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发表时间：
2005-10-01
影响因子：
11.5
通讯作者：
Yang, CS
中科院分区：
文献类型：
--
作者：
Fang, MZ;Chen, DP;Yang, CS
Purpose: We have previously shown the reactivation of some methylation-silenced genes in cancer cells by (-)-epigallocatechin-3-gallate, the major polyphenol from green tea. To determine whether other polyphenolic compounds have similar activities, we studied the effects of soy isoflavones on DNA methylation.Experimental Design: Enzyme assay was used to determine the inhibitory effect of genistein on DNA methyltransferase activity in nuclear extracts and purified recombinant enzyme. Methylation-specific PCR and quantitative real-time PCR were employed to examine the DNA methylation and gene expression status of retinoic acid receptor beta (RAR beta), p16(INK4a), and O-6-methylguanine,methyltransferase (MGMT) in KYSE 510 esophageal squamous cell carcinoma cells treated with genistein alone or in combination with trichostatin, sulforaphane, or 2'-deoxy-5- aza-cyticline (5-aza-dCyd).Results: Genistein (2-20 mu mol/L) reversed DNA hypermethylation and reactivated RAR beta, p16(INK4a), and MGMT in KYSE 510 cells. Genistein also inhibited cell growth at these concentrations. Reversal of DNA hypermethylation and reactivation of RAR beta by genistein were also observed in KYSE 150 cells and prostate cancer LNCaP and PC3 cells. Genistein (20-50 mu mol/L) dose-dependently inhibited DNA methyltransferase activity, showing substrate- and methyl donor-dependent inhibition. Biochanin A and daidzein Were less effective in inhibiting DNA methy transferase activity, in reactivating RAR beta, and in inhibiting cancer cell growth. In combination with trichostatin, sulforaphane, or 5-aza-dCyd, genistein enhanced reactivation of these genes and inhibition of cell growth.Conclusions:These results indicate that genistein and related soy isoflavones reactivate methylation-silenced genes, partially through a direct inhibition of DNA methyltransferase, which may contribute to the chemopreventive activity of dietary isoflavones.
