Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer
Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer
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DOI：
10.1159/000079145
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Imai, K
中科院分区：
文献类型：
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作者：
Ueno, M;Toyota, M;Imai, K
一种钠共转运体，溶质载体家族5成员8基因（SLC5A8）的异常甲基化已经在结直肠癌的一个亚群中被检测到，这表明SLC5A8也可能作为肿瘤抑制因子。为了进一步研究SLC5A8表达的表观遗传失活在胃癌中的作用，我们在一组胃癌细胞系和原发性胃癌中检测了SLC5A8 5' CpG岛（CGI）的甲基化状态。我们在12株胃癌细胞系中检测到10株5' CGI的甲基化，其中5株表现出密集的甲基化，这与SLC5A8转录缺失有关。71例原发性胃癌中有23例（30%）检测到SLC5A8的异常甲基化，这表明SLC5A8的表观遗传失活并不是细胞系特异性现象。用甲基转移酶抑制剂5-aza-2'-脱氧胞苷处理后，SLC5A8在甲基化细胞系中的表达得以恢复。此外，染色质免疫沉淀分析显示，该基因5'区组蛋白H3的乙酰化与SLC5A8的表达直接相关，与DNA甲基化呈负相关。因此，SLC5A8的5' CGI异常甲基化和组蛋白去乙酰化在胃癌中沉默SLC5A8的表达中发挥了关键作用。版权所有(C) 2004 S. Karger AG，巴塞尔。
Aberrant methylation of a sodium co-transporter, solute carrier family 5 member 8 gene (SLC5A8), has been detected in a subset of colorectal cancers, suggesting SLC5A8 may also serve as a tumor suppressor. To further investigate the role of epigenetic inactivation of SLC5A8 expression in gastric cancer, we determined the methylation status of the SLC5A8 5' CpG island (CGI) in a panel of gastric cancer cell lines and primary gastric cancers. We detected methylation of the 5' CGI in ten of twelve gastric cancer cell lines, and five of those showed dense methylation, which correlated with the absence of SLC5A8 transcription. Aberrant methylation of SLC5A8 was also detected in 23 of 71 (30%) primary gastric cancers, indicating that epigenetic inactivation of SLC5A8 is not a cell-line-specific phenomenon. SLC5A8 expression was restored in methylated cell lines by treatment with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor. In addition, chromatin immunoprecipitation assays showed that acetylation of histone H3 in the 5' region of the gene correlated directly with SLC5A8 expression and inversely with DNA methylation. It thus appears that aberrant methylation of its 5' CGI and histone deacetylation play key roles in silencing SLC5A8 expression in gastric cancers. Copyright (C) 2004 S. Karger AG, Basel.