DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers.
DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers.
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DOI：
10.1038/sj.bjc.6600319
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发表时间：
2002-06-05
影响因子：
8.8
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Satoh, A;Toyota, M;Itoh, F;Kikuchi, T;Obata, T;Sasaki, Y;Suzuki, H;Yawata, A;Kusano, M;Fujita, M;Hosokawa, M;Yanagihara, K;Tokino, T;Imai, K
死亡相关蛋白激酶是干扰素γ诱导的程序性细胞死亡的正调节因子。为了研究死亡相关蛋白激酶表观遗传失活在胃肠道癌症中的作用，我们检测了死亡相关蛋白激酶基因5 ' CpG岛的甲基化状态。5 ' CpG岛在9个结直肠癌细胞系中的3个和17个胃癌细胞系中检测到甲基化，而在原发性肿瘤中，28个结直肠癌细胞系中有4个（14%）和27个胃癌细胞系中有4个（15%）检测到甲基化。相比之下，CpG岛边缘的甲基化几乎在每个检测的样本中都被检测到。死亡相关蛋白激酶的表达在4个显示5 ' CpG岛密集甲基化的细胞系中减少，用甲基转移酶抑制剂5-aza-2 ' -脱氧胞苷处理后，基因表达恢复。通过染色质免疫沉淀评估基因5 '区组蛋白H3和H4的乙酰化，发现与基因表达直接相关，与DNA甲基化呈负相关。因此，异常的DNA甲基化和5 ' CpG岛的组蛋白去乙酰化，而不是CpG岛的边缘，似乎在抑制胃肠道恶性肿瘤中死亡相关蛋白激酶的表达中起关键作用。英国癌症杂志（2002）86,1817-1823。doi: 10.1038 / sj.bjc。6600319 www.bjcancer.com©2002英国癌症研究中心
Death-associated protein kinase is a positive regulator of programmed cell death induced by interferon γ. To investigate the role of epigenetic inactivation of death-associated protein kinase in gastrointestinal cancer, we examined the methylation status of the 5′ CpG island of the death-associated protein kinase gene. Methylation of the 5′ CpG island was detected in 3 of 9 colorectal and 3 of 17 gastric cancer cell lines, while among primary tumours, it was detected in 4 of 28 (14%) colorectal and 4 of 27 (15%) gastric cancers. By contrast, methylation of the edge of the CpG island was detected in virtually every sample examined. Death-associated protein kinase expression was diminished in four cell lines that showed dense methylation of the 5′ CpG island, and treatment with 5-aza-2′-deoxycitidine, a methyltransferase inhibitor, restored gene expression. Acetylation of histones H3 and H4 in the 5′ region of the gene was assessed by chromatin immunoprecipitation and was found to correlate directly with gene expression and inversely with DNA methylation. Thus, aberrant DNA methylation and histone deacetylation of the 5′ CpG island, but not the edge of the CpG island, appears to play a key role in silencing death-associated protein kinase expression in gastrointestinal malignancies. British Journal of Cancer (2002) 86, 1817–1823. doi:10.1038/sj.bjc.6600319 www.bjcancer.com © 2002 Cancer Research UK