DNA甲基化和组蛋白乙酰化介导的肿瘤抗凋亡机制与靶向治疗

The anti-apoptotic mechanisms of human cancer mediated by DNA methylation and histone acetylation and the targeted therapies

肿瘤发生发展是复杂且多步骤的过程,是遗传和表观遗传异常共同作用的结果。遗传变异能引起细胞增殖、分化和凋亡通路异常而导致肿瘤发生,越来越多的研究表明,表观遗传改变可引起癌基因的扩增或肿瘤抑制基因的沉默,在癌症的发生发展中同样发挥着重要作用。常见的表观遗传修饰包括基因启动子区域CpG岛甲基化、组蛋白修饰(包括组蛋白乙酰化和甲基化)、非编码RNA调控以及RNA的修饰。这些表观遗传变化不仅影响基因功能,还通过影响肿瘤微环境促使癌症特征的形成(包括持续增殖、抵抗治疗、血管生成、局部侵袭和远处转移)。本综述将重点阐述DNA甲基化和组蛋白乙酰化在介导肿瘤抗凋亡机制中的作用,并将讨论靶向表观遗传因子的抗肿瘤药物的发展现状及前景。

The development of human cancer is a complex and multistep process which result from combinations of genetic and epigenetic abnormalities.While genetic aberrations can lead to cancer through dysregulation of cell proliferation,differentiation,and apoptosis.Emerging evidence revealed that epigenetic alterations also play major roles in human cancer.These epigenetic alterations result in amplification of oncogene expression and silencing of tumor suppressor genes,which play important roles in both cancer development and disease progression.The most common epigenetic modifications observed are increased methylation of CpG islands within gene promoter region,histone modifications including acetylation and/or methylation of histone proteins,expression of noncoding RNAs and RNA modifications.These epigenetic changes not only affect gene functions within the tumor but also influence the microenvironment surrounding the tumor,which culminate the hallmarks of cancer including sustained proliferation,resistance to therapeutics,angiogenesis,local invasion and distant metastasis.Hence,this review mainly focused on the roles of altered DNA methylation and histone acetylation in me-diating anti-apoptotic mechanisms in tumors,and also discussed the development of agents that target epigenetic factors for cancer treatment.