Overexpression of histone deacetylase 1 confers resistance to sodium butyrate-mediated apoptosis in melanoma cells through a p53-mediated pathway
Overexpression of histone deacetylase 1 confers resistance to sodium butyrate-mediated apoptosis in melanoma cells through a p53-mediated pathway
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DOI：
10.1158/0008-5472.can-03-3897
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Medrano, EE
中科院分区：
文献类型：
--
作者：
Bandyopadhyay, D;Mishra, A;Medrano, EE
黑色素瘤细胞通常表达野生型p53，但它们对DNA损伤剂具有众所周知的抗性。在这里，我们表明，丁酸钠（NaB），组蛋白去乙酰化酶（HDAC）抑制剂，诱导人黑色素瘤细胞凋亡的剂量和时间依赖性的方式。凋亡与HDAC 1依赖的Bax诱导和p53的乙酰化有关。通过反义载体下调HDAC 1使细胞对NaB诱导的凋亡敏感，而其过表达赋予对该试剂的抗性。HDAC 1水平和活性的增加损害了NaB介导的Bax启动子和Bax蛋白水平的激活。最后，使用p53-null黑色素瘤细胞系和RNA干扰表达野生型p53蛋白的细胞，我们表明Bax诱导和NaB介导的细胞凋亡是p53依赖性的。
Melanoma cells typically express wild-type p53, yet they are notoriously resistant to DNA-damaging agents. Here, we show that sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor, induced apoptosis in human melanoma cells in a dose- and time-dependent manner. Apoptosis was associated with HDAC1-dependent induction of Bax and acetylation of p53. Down-regulation of HDAC1 by an antisense vector sensitized the cells to NaB-induced apoptosis, whereas its overexpression conferred resistance to this agent. Increased HDAC1 levels and activity impaired NaB-mediated activation of Bax promoter and Bax protein levels. Finally, using p53-null melanoma cell line and RNA interference in cells expressing wild-type p53 protein, we show that Bax induction and NaB-mediated apoptosis is p53 dependent.