Zahnow C A, Topper M, Stone M, Murray-Stewart T, Li H, Baylin S B, Casero R A
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States.
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States.
Adv Cancer Res. 2016;130:55-111. doi: 10.1016/bs.acr.2016.01.007. Epub 2016 Mar 2.
Epigenetic silencing and inappropriate activation of gene expression are frequent events during the initiation and progression of cancer. These events involve a complex interplay between the hypermethylation of CpG dinucleotides within gene promoter and enhancer regions, the recruitment of transcriptional corepressors and the deacetylation and/or methylation of histone tails. These epigenetic regulators act in concert to block transcription or interfere with the maintenance of chromatin boundary regions. However, DNA/histone methylation and histone acetylation states are reversible, enzyme-mediated processes and as such, have emerged as promising targets for cancer therapy. This review will focus on the potential benefits and synergistic/additive effects of combining DNA-demethylating agents and histone deacetylase inhibitors or lysine-specific demethylase inhibitors together in epigenetic therapy for solid tumors and will highlight what is known regarding the mechanisms of action that contribute to the antitumor response.
在癌症的发生和发展过程中，表观遗传沉默和基因表达的不适当激活是常见事件。这些事件涉及基因启动子和增强子区域内CpG二核苷酸的高甲基化、转录共抑制因子的募集以及组蛋白尾部的去乙酰化和/或甲基化之间的复杂相互作用。这些表观遗传调节因子协同作用以阻断转录或干扰染色质边界区域的维持。然而，DNA/组蛋白甲基化和组蛋白乙酰化状态是可逆的、酶介导的过程，因此已成为癌症治疗的有希望的靶点。本综述将重点关注在实体瘤的表观遗传治疗中联合使用DNA去甲基化剂与组蛋白脱乙酰酶抑制剂或赖氨酸特异性去甲基化酶抑制剂的潜在益处和协同/相加作用，并将突出关于促成抗肿瘤反应的作用机制的已知信息。
