Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer
Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer
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DOI：
10.1093/hmg/10.7.687
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发表时间：
2001-04-01
影响因子：
3.5
通讯作者：
Herman, JG
中科院分区：
文献类型：
--
作者：
Baylin, SB;Esteller, M;Herman, JG
癌症中的基因功能可以通过直接突变或删除基因的遗传改变，或者通过改变基因表达的可遗传状态的表观遗传改变来破坏。后一种事件是通过在基因转录起始点周围形成转录抑制染色质状态以及在这些区域的正常未甲基化的CpG岛上相关的甲基化获得介导的。受影响的基因包括超过一半的肿瘤抑制基因，这些基因在胚系中突变时会导致家族性癌症；这些基因对遗传和表观遗传功能障碍的选择优势非常相似。甲基化异常可以在肿瘤进展的早期就开始，并介导大多数重要的癌症通路异常，包括细胞周期控制的丧失、转录因子功能的改变、受体功能的改变、正常细胞-细胞和细胞-底物相互作用的中断、信号转导通路的失活、凋亡信号的丢失和遗传不稳定性。异常甲基化在基因转录沉默中的积极作用越来越为人们所了解，这种作用涉及甲基化和组蛋白脱乙酰酶(HDAC)活性之间的协同作用，这种协同作用可以直接通过HDAC与DNA甲基化酶的相互作用以及通过涉及甲基胞嘧啶结合蛋白的复合体的募集来介导。在翻译领域，启动子超甲基化变化作为DNA肿瘤标志物具有很大的前景，其潜在的可逆状态为涉及基因重新激活的癌症治疗策略创造了一个靶点。
Gene function in cancer can be disrupted either through genetic alterations, which directly mutate or delete genes, or epigenetic alterations, which alter the heritable state of gene expression. The latter events are mediated by formation of transcriptionally repressive chromatin states around gene transcription start sites and an associated gain of methylation in normally unmethylated CpG islands in these regions. The genes affected include over half of the tumor suppressor genes that cause familial cancers when mutated in the germline; the selective advantage for genetic and epigenetic dysfunction in these genes is very similar. The aberrant methylation can begin very early in tumor progression and mediate most of the important pathway abnormalities in cancer including loss of cell cycle control, altered function of transcription factors, altered receptor function, disruption of normal cell-cell and cell-substratum interaction, inactivation of signal transduction pathways, loss of apoptotic signals and genetic instability. The active role of the aberrant methylation in transcriptional silencing of genes is becoming increasingly understood and involves a synergy between the methylation and histone deacetylase (HDAC) activity, This synergy can be mediated directly by HDAC interaction with DNA methylating enzymes and by recruitment through complexes involving methyl-cytosine binding proteins. In the translational arena, the promoter hypermethylation changes hold great promise as DNA tumor markers and their potentially reversible state creates a target for cancer therapeutic strategies involving gene reactivation.