Bandyopadhyay Debdutta, Mishra Anupam, Medrano Estela E
Huffington Center on Aging and Department of Dermatology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Res. 2004 Nov 1;64(21):7706-10. doi: 10.1158/0008-5472.CAN-03-3897.
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.
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。在此，我们表明丁酸钠（NaB），一种组蛋白脱乙酰酶（HDAC）抑制剂，以剂量和时间依赖性方式诱导人黑色素瘤细胞凋亡。细胞凋亡与HDAC1依赖性的Bax诱导和p53的乙酰化有关。反义载体下调HDAC1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。HDAC1水平和活性的增加损害了NaB介导的Bax启动子激活和Bax蛋白水平。最后，使用p53缺失的黑色素瘤细胞系并在表达野生型p53蛋白的细胞中进行RNA干扰，我们表明Bax诱导和NaB介导的凋亡是p53依赖性的。
