Reactivating the expression of methylation silenced genes in human cancer
Reactivating the expression of methylation silenced genes in human cancer
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DOI：
10.1038/sj.onc.1205602
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发表时间：
2002-08-12
期刊：
影响因子：
8
通讯作者：
Jones, DA
中科院分区：
文献类型：
--
作者：
Karpf, AR;Jones, DA
DNA甲基化改变现在被广泛认为是人类肿瘤发生的一个促成因素。大量的肿瘤抑制基因转录沉默的启动子超甲基化，最近的研究表明，染色质结构的改变，这种抑制的机制基础。负责催化DNA-胞嘧啶甲基化的酶，以及参与解释DNA甲基化信号的蛋白质，现在已经被阐明。技术进步，包括基因表达微阵列和基因组扫描技术，已经允许全面测量人类癌症中的DNA甲基化变化。DNA甲基化（表观遗传）和突变或缺失（遗传）肿瘤抑制基因失活之间的一个重要区别是，表观遗传失活可以被小分子消除，包括DNA甲基转移酶和组蛋白脱乙酰酶抑制剂。此外，已经开发了将联合收割机治疗与重新激活沉默的基因表达的药物和靶向重新表达的基因和/或重建的信号转导途径的第二试剂组合的策略。在这篇综述中，我们将详细讨论基因沉默的DNA甲基化的机制，用于破译人类癌症中甲基化失活基因的互补的技术，以及重新激活甲基化沉默基因表达的当前和未来的策略。
DNA methylation alterations are now widely recognized as a contributing factor in human tumorigenesis. A significant number of tumor suppressor genes are transcriptionally silenced by promoter hypermethylation, and recent research implicates alterations in chromatin structure as the mechanistic basis for this repression. The enzymes responsible for catalyzing DNA-cytosine methylation, as well as the proteins involved in interpreting the DNA methylation signal, have now been elucidated. Technological advances, including gene expression microarrays and genome scanning techniques, have allowed the comprehensive measurement of DNA methylation changes in human cancers. An important distinction between DNA methylation (epigenetic) and mutation or deletion (genetic) tumor suppressor gene inactivation is that epigenetic inactivation can be abrogated by small molecules, including DNA methyltransferase and histone deacetylase inhibitors. Further, strategies have been developed that combine treatments with drugs that reactivate silenced gene expression with secondary agents that target the re-expressed genes and/or reconstituted signal transduction pathways. In this review, we will discuss in detail the mechanisms of gene silencing by DNA methylation, the techniques used to decipher the complement of methylation-inactivated genes in human cancers, and current and future strategies for reactivating the expression of methylation-silenced genes.