Harvard-MIT Division of Health Sciences and Technology, Bioinformatics & Integrative Genomics, Cambridge, MA 02115, USA.
Oncogene. 2012 Mar 1;31(9):1181-8. doi: 10.1038/onc.2011.307. Epub 2011 Aug 1.
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.
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。许多研究已经报道了具有已知致癌作用的个别基因的甲基化状态，但迄今为止尚未对高甲基化基因的集体生物学功能进行无偏评估。基于这样一种观察结果，即多种人类癌症重现了发育基因表达模式（即激活通常在早期发育中表达的基因，并抑制晚期发育基因），我们假设癌症中与分化相关的基因沉默部分归因于 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发育晚期表达的基因。对这些基因的基因本体论特征分析表明，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 高甲基化作为一种选择性沉默机制，作用于维持分化状态所需的基因。在癌症中，无论是在微观水平还是转录水平上，细胞去分化的过程至少部分可能是由这些表观遗传事件介导的。我们的观察结果为用 DNA 甲基转移酶抑制剂治疗诱导分化提供了一种机制解释。
