Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer
Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer
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DOI：
10.1038/sj.onc.1207576
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发表时间：
2004-05-27
期刊：
影响因子：
8
通讯作者：
Mukai, T
中科院分区：
文献类型：
--
作者：
Soejima, H;Nakagawachi, T;Mukai, T
推测的肿瘤抑制基因CDKN1C是11p15.5的印记基因，这是一个在肿瘤中经常缺失的众所周知的印记区域。CDKN1C在肿瘤中没有体细胞突变和经常表达减弱，这表明CDKN1C的表达是受表观遗传调控的。然而，CDKN1C/LIT1结构域的印迹破坏还是CDKN1C本身的启动子高甲基化导致了CDKN1C的减少一直存在争议。为了阐明这一点，我们研究了CDKN1C启动子的CpG甲基化指数和LIT1 CpG岛的差异甲基化区域(差异甲基化区域(DMR)-LIT1)，以及该区域的印记控制区，以及CDKN1C在食管癌细胞系中的表达。CDKN1C在17株肿瘤中有10株表达降低，并且除3株外，其余均与DMR-LIT1基因甲基化缺失有关。CDKN1C启动子MI与CDKN1C表达无统计学相关性。此外，在DMR-LIT1，CpG甲基化缺失与组蛋白H3赖氨酸9(H3K9)甲基化缺失相关。组蛋白·莫迪。CDKN1C启动子上的阳离子与CDKN1C的表达无关。这些数据表明，CDKN1C表达的降低与DMR-LIT1上CpG和H3K9的甲基化缺失有关，而不是通过其自身的启动子CpG甲基化，并参与了食道癌的发生。这意味着DMR-LIT1不是通过CDKN1C启动子上的组蛋白修饰，而是通过DMR-LIT1的组蛋白修饰来调控CDKN1C的表达。
The putative tumor suppressor CDKN1C is an imprinted gene at 11p15.5, a well-known imprinted region often deleted in tumors. The absence of somatic mutations and the frequent diminished expression in tumors would suggest that CDKN1C expression is regulated epigenetically. It has been, however, controversial whether the diminution is caused by imprinting disruption of the CDKN1C/LIT1 domain or by promoter hypermethylation of CDKN1C itself. To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines. CDKN1C expression was diminished in 10 of 17 lines and statistically correlated with the loss of methylation at DMR-LIT1 in all but three. However, there was no statistical correlation between CDKN1C promoter MI and CDKN1C expression. Furthermore, loss of CpG methylation was associated with loss of histone H3 lysine 9 (H3K9) methylation at DMR-LIT1. Histone modi. cations at CDKN1C promoter were not correlated with CDKN1C expression. The data suggested that the diminished CDKN1C expression is associated with the loss of methylation of CpG and H3K9 at DMR-LIT1, not by its own promoter CpG methylation, and is involved in esophageal cancer, implying that DMR-LIT1 epigenetically regulates CDKN1C expression not through histone modifications at CDKN1C promoter, but through that of DMR-LIT1.