DNA hypermethylation in lung cancer is targeted at differentiation-associated genes
DNA hypermethylation in lung cancer is targeted at differentiation-associated genes
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DOI：
10.1038/onc.2011.307
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发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
Kohane, I. S.
中科院分区：
文献类型：
--
作者：
Helman, E.;Naxerova, K.;Kohane, I. S.
肿瘤抑制基因的异常 DNA 高甲基化被认为是肿瘤发生的早期事件。许多研究报告了已知与癌症有关的单个基因的甲基化状态，但迄今为止尚未对高甲基化基因集合的生物学功能进行公正的评估。基于对多种人类癌症重演发育基因表达模式（即激活早期发育中正常表达的基因并抑制晚期发育基因）的观察，我们假设癌症中分化相关基因的沉默可能部分归因于 DNA 高甲基化。为此，我们研究了原发性人肺癌和肺癌细胞系中具有高甲基化 CpG 岛的基因的发育表达模式。我们发现 DNA 高甲基化主要影响在小鼠肺部发育后期表达的基因。这些基因的基因本体表征表明它们几乎完全参与形态发生分化过程。我们的结果表明，癌症中的 DNA 高甲基化充当维持分化状态所需的基因的选择性沉默机制。在癌症的微观和转录水平上都很明显的细胞去分化过程可能至少部分是由这些表观遗传事件介导的。我们的观察结果为 DNA 甲基转移酶抑制剂治疗后诱导分化提供了机制解释。癌基因 (2012) 31, 1181-1188; doi：10.1038/onc.2011.307； 2011 年 8 月 1 日在线发布
Aberrant DNA hypermethylation of tumor suppressor genes is thought to be an early event in tumorigenesis. Many studies have reported the methylation status of individual genes with known involvement in cancer, but an unbiased assessment of the biological function of the collective of hypermethylated genes has not been conducted so far. Based on the observation that a variety of human cancers recapitulate developmental gene expression patterns ( that is activate genes normally expressed in early development and suppress late developmental genes), we hypothesized that the silencing of differentiation-associated genes in cancer could be attributed in part to DNA hypermethylation. To this end, we investigated the developmental expression patterns of genes with hypermethylated CpG islands in primary human lung carcinomas and lung cancer cell lines. We found that DNA hypermethylation primarily affects genes that are expressed in late stages of murine lung development. Gene ontology characterization of these genes shows that they are almost exclusively involved in morphogenetic differentiation processes. Our results indicate that DNA hypermethylation in cancer functions as a selective silencing mechanism of genes that are required for the maintenance of a differentiated state. The process of cellular de-differentiation that is evident on both the microscopic and transcriptional level in cancer might at least partly be mediated by these epigenetic events. Our observations provide a mechanistic explanation for induction of differentiation upon treatment with DNA methyltransferase inhibitors. Oncogene (2012) 31, 1181-1188; doi:10.1038/onc.2011.307; published online 1 August 2011