Bmf contributes to histone deacetylase inhibitor-mediated enhancing effects on apoptosis after ionizing radiation
Bmf contributes to histone deacetylase inhibitor-mediated enhancing effects on apoptosis after ionizing radiation
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DOI：
10.1007/s10495-006-8266-1
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发表时间：
2006-08-01
期刊：
影响因子：
7.2
通讯作者：
Shinomura, Yasuhisa
中科院分区：
文献类型：
--
作者：
Zhang, Yubin;Adachi, Masaaki;Shinomura, Yasuhisa
组蛋白去乙酰化酶（HDAC）抑制剂通过不确定的机制增强电离辐射（IR）诱导的几种癌细胞凋亡。我们最近发现HDAC抑制剂在人鳞状细胞癌SAS细胞中诱导仅BH3蛋白Bmf。我们扩展了这项研究，发现2.5 nM FK228预处理不能诱导细胞凋亡，但增加了IR诱导的死亡。FK228预处理增加Bmf表达水平，siRNA介导的Bmf转录本的敲低强烈抑制其增强IR诱导的细胞死亡、线粒体膜电位破坏和DNA片段化。另一种HDAC抑制剂CBHA预处理类似地增强IR诱导的细胞凋亡，并且这种作用也被Bmf敲低抑制。Bmf过表达增强IR诱导的细胞死亡，在另一种鳞状细胞癌HSC 2细胞中观察到类似的FK228增强效应。组蛋白乙酰转移酶p300的过表达模拟了HDAC抑制剂的作用，即，它增强了IR诱导的死亡，这主要被Bmf敲低所消除。综上所述，组蛋白超乙酰化可能通过激活Bmf转录来增强IR诱导的细胞死亡，从而暗示Bmf是HDAC抑制剂（FK228和CBHA）介导的对IR诱导的细胞死亡的增强作用的关键分子。
Histone deacetylase (HDAC) inhibitors augment ionizing radiation (IR)-induced apoptosis in several cancer cells by undefined mechanism(s). We recently found that the HDAC inhibitors induce a BH3-only protein Bmf in human squamous carcinoma SAS cells. We extended this study and found that 2.5 nM FK228 pretreatment could not induce apoptosis but augmented IR-induced death. The FK228 pretreatment increased Bmf expression level, and siRNA-mediated knockdown of Bmf transcripts strongly inhibited its augmentation of IR-induced cell death, disruption of mitochondrial membrane potential and DNA fragmentation. Another HDAC inhibitor CBHA pretreatment similarly augmented IR-induced apoptosis, and this effect was also inhibited by Bmf knockdown. Bmf overexpression augmented IR-induced death, and the augmented effects of FK228 were similarly observed in another squamous carcinoma HSC2 cells. Overexpression of histone acetyltransferase p300 mimicked the effects of the HDAC inhibitors, i.e., it enhanced IR-induced death, which was mostly abolished by Bmf knockdown. Taken together, histone hyperacetylation may enhance IR-induced death via activation of Bmf transcription, thereby implying Bmf as a key molecule for HDAC inhibitors (FK228 and CBHA)-mediated enhancing effect on IR-induced cell death.