Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells.
Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells.
复制标题
DOI：
10.1093/carcin/bgn179
复制
发表时间：
2008-11
期刊：
影响因子：
4.7
通讯作者：
Nong Xiang;R. Zhao;Guoqing Song;Weixiong Zhong
中科院分区：
文献类型：
--
作者：
Nong Xiang;R. Zhao;Guoqing Song;Weixiong Zhong
DNA高甲基化是人类前列腺癌常见的表观遗传学改变，被认为与前列腺癌的发展有关。越来越多的数据表明，饮食因素可能通过改变细胞内的表观遗传过程来改变癌症风险。本研究旨在研究硒(Se)是否会改变表观遗传学事件，以调节人类前列腺癌细胞中甲基化沉默的基因。采用聚合酶链式反应、蛋白质印迹分析、染色质免疫沉淀法和酶活力测定等方法，研究了亚硒处理后LNCaP细胞DNA甲基化、组蛋白修饰和基因表达的变化。我们的研究表明，亚硒处理导致LNCaP细胞部分启动子DNA去甲基化和pi类谷胱甘肽-S转移酶的重新表达，并呈剂量和时间依赖关系。亚硒处理降低了DNA甲基转移酶(DNMTs)1和3A的信使RNA水平以及DNMT1的蛋白水平。亚硒酸盐还降低了组蛋白脱乙酰酶活性，增加了组蛋白H3(H3-Lys 9)上乙酰化赖氨酸9的水平，但降低了与GSTP1启动子相关的DNMT1和甲基化H3-Lys 9的水平。此外，亚硒酸盐治疗降低了总DNA甲基化，并导致部分启动子去甲基化和肿瘤抑制基因腺瘤性息肉病结肠和细胞应激反应1的重新表达，细胞应激反应1是一种与肿瘤生长和转移有关的基因。我们的研究表明，硒可以在表观遗传上调节DNA和组蛋白，以激活甲基化沉默的基因。这些表观遗传修饰可能有助于硒预防癌症。
DNA hypermethylation is a common epigenetic alteration in human prostate cancer and is considered to contribute to development of this disease. Accumulating data suggest that dietary factors may alter cancer risk by modifications of epigenetic processes in the cell. The present study was designed to investigate whether selenium (Se) would alter epigenetic events to regulate methylation-silenced genes in human prostate cancer cells. DNA methylation, histone modifications and gene expression were studied in LNCaP cells after selenite treatment using polymerase chain reaction, western blot analysis, chromatin immunoprecipitation assay and enzymatic activity assay. Our study shows that selenite treatment caused partial promoter DNA demethylation and reexpression of the pi-class glutathione-S-transferase (GSTP1) in LNCaP cells in a dose- and time-dependent manner. Selenite treatment decreased messenger RNA levels of DNA methyltransferases (DNMTs) 1 and 3A and protein levels of DNMT1. Selenite also decreased histone deacetylase activity and increased levels of acetylated lysine 9 on histone H3 (H3-Lys 9), but decreased levels of methylated H3-Lys 9. Selenite treatment reduced levels of DNMT1 and methylated H3-Lys 9 associated with the GSTP1 promoter, but increased levels of acetylated H3-Lys 9 associated with this promoter. Additionally, selenite treatment decreased general DNA methylation and caused partial promoter demethylation and reexpression of the tumor suppressor adenomatous polyposis coli and cellular stress response 1, a gene involving tumor growth and metastasis. Our study demonstrates that Se can epigenetically modulate DNA and histones to activate methylation-silenced genes. These epigenetic modifications may contribute to cancer prevention by Se.