Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells.
Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells.
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DOI：
10.1002/ijc.24988
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发表时间：
2010-06-01
影响因子：
6.4
通讯作者：
Gupta, Sanjay
中科院分区：
文献类型：
--
作者：
Pandey, Mitali;Shukla, Sanjeev;Gupta, Sanjay
谷胱甘肽-S-转移酶p1的表观遗传沉默被认为是人类前列腺癌的分子标志。我们观察了绿茶多酚(GTP)对GSTP1再表达的影响，并与DNA甲基转移酶(DNMT)核苷类似物5-氮杂-2‘脱氧胞苷(5-aza-2’deoxcitidine)相比较，进一步阐明了其作用机制和长期安全性。人前列腺癌LNCaP细胞暴露于1-10μg/mLGTP 1-7天后，GSTP1二次表达呈浓度和时间依赖性，与DNMT1抑制相关。甲基特异性聚合酶链式反应和测序显示，GSTP1启动子近端和转录因子结合位点远端区域存在广泛的去甲基化。GTP以时间依赖的方式降低MBD1、MBD4和MeCP2、HDAC1-3的mRNA和蛋白水平，并增加乙酰化组蛋白H3(LysH9/18)和H4的水平。染色质免疫沉淀分析表明，经GTP处理的细胞减少了Mbd2与可访问的Sp1结合位点的结合，从而增加了GSTP1基因的结合和转录激活。正如LINE-1启动子的甲基特异性聚合酶链式反应所证明的那样，细胞暴露于GTP并没有导致全球低甲基化；相反，GTP促进了基因组完整性的维持。此外，细胞暴露在GTP中并不会导致促转移基因S100P的激活，这是在细胞暴露于5-氮杂-2‘脱氧胞苷后出现的反向反应。我们的结果首次证明，GTP具有改变DNA甲基化和染色质建模的双重潜力，这两种基因调控的全球表观遗传机制，以及它们的无毒性使它们成为前列腺癌化学预防的极佳候选者。
Epigenetic silencing of gluthathione-S-transferase pi (GSTP1) is recognized as being a molecular hallmark of human prostate cancer. We investigated the effects of green tea polyphenols (GTP) on GSTP1 re-expression and further elucidated its mechanism of action and long-term safety, compared with nucleoside-analog inhibitor of DNA methyltransferase (DNMT), 5-aza-2′deoxycitidine. Exposure of human prostate cancer LNCaP cells to 1–10μg/mL of GTP for 1–7 days caused a concentration- and time-dependent re-expression of GSTP1 which correlated with DNMT1 inhibition. Methyl-specific-PCR and sequencing revealed extensive demethylation in the proximal GSTP1 promoter and regions distal to the transcription factor binding sites. GTP exposure in a time-dependent fashion diminished the mRNA and protein levels of MBD1, MBD4 and MeCP2; HDAC 1–3 and increased the levels of acetylated histone H3 (LysH9/18) and H4. Chromatin immunoprecipitation assays demonstrated that cells treated with GTP have reduced MBD2 association with accessible Sp1 binding sites leading to increased binding and transcriptional activation of the GSTP1 gene. Exposure of cells to GTP did not result in global hypomethylation, as demonstrated by methyl-specific PCR for LINE-1 promoter; rather, GTP promotes maintenance of genomic integrity. Furthermore, exposure of cells to GTP did not cause activation of the pro-metaststic gene S100P, a reverse response noted after exposure of cells to 5-aza-2′deoxycitidine. Our results, for the first time, demonstrate that GTP has dual potential to alter DNA methylation and chromatin modeling, the two global epigenetic mechanisms of gene regulation, and their lack of toxicity makes them excellent candidates for the chemoprevention of prostate cancer.
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