Baylin S B, Esteller M, Rountree M R, Bachman K E, Schuebel K, Herman J G
The Johns Hopkins Comprehensive Cancer Center and Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Hum Mol Genet. 2001 Apr;10(7):687-92. doi: 10.1093/hmg/10.7.687.
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.
癌症中的基因功能可通过基因改变或表观遗传改变而被破坏，基因改变直接使基因发生突变或缺失，表观遗传改变则改变基因表达的可遗传状态。后一种情况是由基因转录起始位点周围转录抑制性染色质状态的形成以及这些区域中正常未甲基化的CpG岛甲基化增加介导的。受影响的基因包括超过一半的肿瘤抑制基因，这些基因在种系中发生突变时会导致家族性癌症；这些基因中遗传和表观遗传功能障碍的选择优势非常相似。异常甲基化可在肿瘤进展的早期就开始，并介导癌症中大多数重要的通路异常，包括细胞周期控制丧失、转录因子功能改变、受体功能改变、正常细胞间和细胞与基质相互作用的破坏、信号转导通路失活、凋亡信号丧失以及基因不稳定。异常甲基化在基因转录沉默中的积极作用越来越被人们所理解，它涉及甲基化与组蛋白脱乙酰酶（HDAC）活性之间的协同作用。这种协同作用可直接由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物募集来介导。在转化领域，启动子高甲基化变化作为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。
