Taberlay Phillippa C, Jones Peter A
Department of Urology, Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Prog Drug Res. 2011;67:1-23. doi: 10.1007/978-3-7643-8989-5_1.
DNA methylation acts in concert with other epigenetic mechanisms to regulate normal gene expression and facilitate chromatin organization within cells. Aberrant DNA methylation patterns are acquired during carcinogenic transformation; such events are often accompanied by alterations in chromatin structure at gene regulatory regions. The expression pattern of any given gene is achieved by interacting epigenetic mechanisms. First, the insertion of nucleosomes at transcriptional start sites prevents the binding of the transcriptional machinery and additional cofactors that initiate gene expression. Second, nucleosomes anchor all of the DNMT3A and DNMT3B methyltransferase proteins in the cell, which suggests a role for histone octamers in the establishment of DNA methylation patterns. During carcinogenesis, epigenetic switching and 5-methylcytosine reprogramming result in the aberrant hypermethylation of CpG islands, reducing epigenetic plasticity of critical developmental and tumor suppressor genes, rendering them unresponsive to normal stimuli. Here, we will discuss the importance of both established and novel molecular concepts that may underlie the role of DNA methylation in cancer.
DNA甲基化与其他表观遗传机制协同作用，以调节正常基因表达并促进细胞内染色质的组织。致癌转化过程中会出现异常的DNA甲基化模式；此类事件通常伴随着基因调控区域染色质结构的改变。任何给定基因的表达模式都是通过相互作用的表观遗传机制实现的。首先，转录起始位点处核小体的插入会阻止启动基因表达的转录机制和其他辅因子的结合。其次，核小体将细胞中的所有DNMT3A和DNMT3B甲基转移酶蛋白固定下来，这表明组蛋白八聚体在DNA甲基化模式的建立中发挥作用。在致癌过程中，表观遗传转换和5-甲基胞嘧啶重编程会导致CpG岛异常高甲基化，降低关键发育基因和肿瘤抑制基因的表观遗传可塑性，使其对正常刺激无反应。在此，我们将讨论既定的和新的分子概念的重要性，这些概念可能是DNA甲基化在癌症中作用的基础。
