Ozyerli-Goknar Ezgi, Bagci-Onder Tugba
Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey.
Research Center for Translational Medicine, Koç University, Istanbul 34450, Turkey.
Cancers (Basel). 2021 Jun 27;13(13):3210. doi: 10.3390/cancers13133210.
Cancer cells possess the ability to evade apoptosis. Genetic alterations through mutations in key genes of the apoptotic signaling pathway represent a major adaptive mechanism of apoptosis evasion. In parallel, epigenetic changes via aberrant modifications of DNA and histones to regulate the expression of pro- and antiapoptotic signal mediators represent a major complementary mechanism in apoptosis regulation and therapy response. Most epigenetic changes are governed by the activity of chromatin modifying enzymes that add, remove, or recognize different marks on histones and DNA. Here, we discuss how apoptosis signaling components are deregulated at epigenetic levels, particularly focusing on the roles of chromatin-modifying enzymes in this process. We also review the advances in cancer therapies with epigenetic drugs such as DNMT, HMT, HDAC, and BET inhibitors, as well as their effects on apoptosis modulation in cancer cells. Rewiring the epigenome by drug interventions can provide therapeutic advantage for various cancers by reverting therapy resistance and leading cancer cells to undergo apoptotic cell death.
癌细胞具有逃避细胞凋亡的能力。通过凋亡信号通路关键基因突变引起的基因改变是逃避细胞凋亡的主要适应性机制。与此同时，通过DNA和组蛋白的异常修饰来调节促凋亡和抗凋亡信号介质的表达的表观遗传变化，是细胞凋亡调节和治疗反应中的主要补充机制。大多数表观遗传变化受染色质修饰酶活性的调控，这些酶在组蛋白和DNA上添加、去除或识别不同的标记。在此，我们讨论凋亡信号成分在表观遗传水平上是如何失调的，特别关注染色质修饰酶在这一过程中的作用。我们还综述了使用表观遗传药物（如DNA甲基转移酶（DNMT）、组蛋白甲基转移酶（HMT）、组蛋白去乙酰化酶（HDAC）和溴结构域和额外末端结构域（BET）抑制剂）进行癌症治疗的进展，以及它们对癌细胞凋亡调节的影响。通过药物干预重塑表观基因组可以通过逆转治疗耐药性并使癌细胞发生凋亡性细胞死亡，为各种癌症提供治疗优势。
