Apoptotic and autophagic cell death induced by histone deacetylase inhibitors
Apoptotic and autophagic cell death induced by histone deacetylase inhibitors
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DOI：
10.1073/pnas.0408345102
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发表时间：
2004-12-28
影响因子：
11.1
通讯作者：
Jiang, XJ
中科院分区：
文献类型：
--
作者：
Shao, YF;Gao, ZH;Jiang, XJ
组蛋白去乙酰化酶（HDAC）抑制剂可以诱导癌细胞的程序性细胞死亡，但其潜在机制尚不清楚。在这项研究中，我们表明两种不同的HDAC抑制剂丁酸盐和辛二酰苯胺异羟肟酸（SAHA）在多种人类癌细胞系中诱导半胱天冬酶-3激活和细胞死亡。caspase-3的激活是通过线粒体/细胞色素c介导的凋亡途径，因为它在敲除Apaf-1（途径的基本介质）的小鼠胚胎成纤维细胞中被废除。HeLa细胞中Bcl-XL的过表达也阻断了HDAC抑制剂对半胱天冬酶的激活。然而，Apaf-1敲除、Bcl-XL过表达和caspase活性的药理学抑制并不能阻止SARA和丁酸盐诱导的细胞死亡。经历这种半胱天冬酶非依赖性死亡的细胞具有明确的自噬细胞死亡的形态特征。因此，HDAC抑制剂可以诱导细胞凋亡和半胱天冬酶非依赖性自噬细胞死亡。通过HDAC抑制剂诱导自噬细胞死亡在治疗具有凋亡缺陷的癌症中具有明确的临床意义。
Histone deacetylase (HDAC) inhibitors can induce programmed cell death in cancer cells, although the underlying mechanism is obscure. In this study, we show that two distinct HDAC inhibitors, butyrate and suberoylanilide hydroxamic acid (SAHA), induced caspase-3 activation and cell death in multiple human cancer cell lines. The activation of caspase-3 was via the mitochondria/cytochrome c-mediated apoptotic pathway because it was abrogated in mouse embryonic fibroblasts with knockout of Apaf-1, the essential mediator of the pathway. Overexpression of Bcl-XL in HeLa cells also blocked caspase activation by the HDAC inhibitors. Nevertheless, Apaf-1 knockout, overexpression of Bcl-XL, and pharmacological inhibition of caspase activity did not prevent SARA and butyrate-induced cell death. The cells undergoing such caspase-independent death had unambiguous morphological features of autophagic cell death. Therefore, HDAC inhibitors can induce both mitochondria-mediated apoptosis and caspase-independent autophagic cell death. Induction of autophagic cell death by HDAC inhibitors has clear clinical implications in treating cancers with apoptotic defects.