Definition of the Landscape of Promoter DNA Hypomethylation in Liver Cancer
Definition of the Landscape of Promoter DNA Hypomethylation in Liver Cancer
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DOI：
10.1158/0008-5472.can-10-3823
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发表时间：
2011-09-01
期刊：
影响因子：
11.2
通讯作者：
Szyf, Moshe
中科院分区：
文献类型：
--
作者：
Stefanska, Barbara;Huang, Jian;Szyf, Moshe
我们以人类最常见的癌症之一--肝细胞癌为模型，描绘了癌症中启动子低甲基化的图景。利用甲基化DNA免疫沉淀和与全面启动子阵列杂交的组合，我们已经鉴定了大约3,700个在肿瘤样本中低甲基化的启动子。低甲基化的启动子出现在整个基因组的簇状中，这表明一个高水平的组织是癌症表观基因组变化的基础。在正常肝脏中，大多数低甲基化启动子表现出中等水平的甲基化和表达，然而，高CpG密度的启动子显示出最明显的基因表达增加。去甲基化的基因主要参与细胞生长、细胞黏附和通讯、信号转导、迁移和侵袭；这些功能是癌症进展和转移所必需的。DNA甲基化抑制剂5-氮杂-2‘-脱氧胞苷激活了几个在肿瘤中被去甲基化和诱导的基因，支持了去甲基化在这些基因激活中的因果作用。以前的研究表明，Mbd2参与了特定人类乳腺癌和前列腺癌基因的去甲基化。然而，在正常肝细胞中，Mbd2缺失几乎或没有影响，我们发现它在人肝癌和腺癌细胞中的缺失导致细胞生长抑制、锚定非依赖性生长和侵袭性，以及启动子甲基化增加和肿瘤中几个低甲基化基因的沉默。综上所述，这些发现定义了低甲基化在癌症中的潜在功能作用。癌症资源；71(17)；5891-903。(C)2011年AACR。
We use hepatic cellular carcinoma (HCC), one of the most common human cancers, as a model to delineate the landscape of promoter hypomethylation in cancer. Using a combination of methylated DNA immunoprecipitation and hybridization with comprehensive promoter arrays, we have identified approximately 3,700 promoters that are hypomethylated in tumor samples. The hypomethylated promoters appeared in clusters across the genome suggesting that a high-level organization underlies the epigenomic changes in cancer. In normal liver, most hypomethylated promoters showed an intermediate level of methylation and expression, however, high-CpG dense promoters showed the most profound increase in gene expression. The demethylated genes are mainly involved in cell growth, cell adhesion and communication, signal transduction, mobility, and invasion; functions that are essential for cancer progression and metastasis. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine, activated several of the genes that are demethylated and induced in tumors, supporting a causal role for demethylation in activation of these genes. Previous studies suggested that MBD2 was involved in demethylation of specific human breast and prostate cancer genes. Whereas MBD2 depletion in normal liver cells had little or no effect, we found that its depletion in human HCC and adenocarcinoma cells resulted in suppression of cell growth, anchorage-independent growth and invasiveness as well as an increase in promoter methylation and silencing of several of the genes that are hypomethylated in tumors. Taken together, the findings define the potential functional role of hypomethylation in cancer. Cancer Res; 71(17); 5891-903. (C) 2011 AACR.