Center for Epigenetics, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.
Int J Mol Sci. 2018 Apr 12;19(4):1166. doi: 10.3390/ijms19041166.
Human malignant tumors are characterized by pervasive changes in the patterns of DNA methylation. These changes include a globally hypomethylated tumor cell genome and the focal hypermethylation of numerous 5'-cytosine-phosphate-guanine-3' (CpG) islands, many of them associated with gene promoters. It has been challenging to link specific DNA methylation changes with tumorigenesis in a cause-and-effect relationship. Some evidence suggests that cancer-associated DNA hypomethylation may increase genomic instability. Promoter hypermethylation events can lead to silencing of genes functioning in pathways reflecting hallmarks of cancer, including DNA repair, cell cycle regulation, promotion of apoptosis or control of key tumor-relevant signaling networks. A convincing argument for a tumor-driving role of DNA methylation can be made when the same genes are also frequently mutated in cancer. Many of the most commonly hypermethylated genes encode developmental transcription factors, the methylation of which may lead to permanent gene silencing. Inactivation of such genes will deprive the cells in which the tumor may initiate from the option of undergoing or maintaining lineage differentiation and will lock them into a perpetuated stem cell-like state thus providing an additional window for cell transformation.
人类恶性肿瘤的特征是 DNA 甲基化模式的普遍改变。这些变化包括整个肿瘤细胞基因组的低甲基化和许多 5'-胞嘧啶-磷酸-鸟嘌呤-3'（CpG）岛的局灶性高甲基化，其中许多与基因启动子有关。将特定的 DNA 甲基化变化与因果关系中的肿瘤发生联系起来一直具有挑战性。一些证据表明，癌症相关的 DNA 低甲基化可能会增加基因组不稳定性。启动子的高甲基化事件可能导致在反映癌症特征的途径中起作用的基因沉默，包括 DNA 修复、细胞周期调控、促进细胞凋亡或控制关键的肿瘤相关信号网络。当相同的基因在癌症中也经常发生突变时，可以提出 DNA 甲基化在肿瘤驱动中的作用的令人信服的论点。许多最常被高甲基化的基因编码发育转录因子，其甲基化可能导致基因的永久沉默。这种基因的失活将剥夺肿瘤可能起始的细胞进行或维持谱系分化的选择，并将其锁定在持续的干细胞样状态，从而为细胞转化提供另一个窗口。
