摘要
组蛋白乙酰基化和去乙酰基化是一种常见的表观遗传修饰方式。组蛋白去乙酰基酶(histone deacetylase,HDAC)是重要的组蛋白乙酰基化调控因子,在很多癌症组织中过高表达。研究表明,HDAC抑制剂能显著地诱导不同组织来源的癌细胞凋亡,但在同样的浓度下,对正常细胞的毒性作用很小,是一类潜在的具有良好应用前景的新型抗肿瘤化合物。因此,了解HDAC抑制剂诱导癌细胞凋亡的分子机制对于其用于癌症的治疗具有重要的参考指导意义。目前已知的HDAC抑制剂可通过下述几种分子途径诱导癌细胞的凋亡:(1)一些促凋亡蛋白的编码基因的启动子区域发生了乙酰化水平的减低,使得这些基因的表达水平相应减少,癌细胞得以存活和增殖。HDAC抑制剂可以上调这些促凋亡蛋白编码基因启动子区域的组蛋白乙酰基化来诱导这些蛋白的表达,从而引起细胞凋亡。(2)有些参与调节细胞凋亡的非组蛋白的活性依赖于自身的乙酰基化状态,而HDAC抑制剂能够上调这些非组蛋白的乙酰基化水平,改变这些蛋白质的生物学活性而导致细胞凋亡。(3)HDAC抑制剂还可以通过一定机制提高细胞内活性氧水平,或者抑制细胞内核因子kB信号通路的活性来诱导癌细胞凋亡。本文就HDAC-抑制剂诱导肿瘤细胞凋亡的分子机制的主要相关背景和进展作一简单介绍。
Histone acetylation is a common epigenetic modification. Histone deacetylases （HDACs） are significant histone acetylation regulatory factors and overexpressed in a variety of cancer tissues. HDAC inhibitors are potent apoptosis inducers to many types of cancer cells, but they have no obvious cytotoxic effect to untransformed cells in the same concentration. Therefore, they are a class of promising anti-cancer reagents. Understanding the molecular mechanism underlying HDAC inhibitor-induced cancer cell apoptosis is crucial for the clinical application of these reagents. Briefly, HDAC inhibitors induce cancer cell apoptosis through the molecular pathways as mentioned below. First, the promoter regions of some proapoptotic genes are hypoacetylated, which represses their expression and maintains cancer cell survival and proliferation. HDAC inhibitors upregulate histone acetylation levels in the promoter regions of these genes and induce their expression and cell apoptosis. Second, the activity of some non-histone proteins involved in apoptosis regulation depends on their acetylation status. HDAC inhibitors upregulate the acetylation levels of these proteins, change their biological activities and result in cell apoptosis. Third, HDAC inhibitors are able to induce cancer cell apoptosis via increasing cellular reactive oxygen species （ROS） or suppressing the activity of NF-KB signaling pathway. Here, we summarize the background and recent advances of the molecular mechanisms underlying HDAC inhibitor-induced cancer cell apoptosis.
出处
《生命的化学》
CAS
CSCD
北大核心
2011年第6期765-771,共7页
Chemistry of Life
