Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis
Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis
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DOI：
10.1038/sj.cdd.4401686
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发表时间：
2006-01-01
影响因子：
12.4
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Zhang, Y;Adachi, M;Imai, K
组蛋白脱乙酰酶(HDAC)抑制剂可修饰选定基因的转录，最终诱导细胞凋亡。然而，其促凋亡活性的分子机制仍不清楚。我们在这里证明了HDAC抑制剂FK228和CBHA在广泛的癌细胞中优先上调BH3-Only蛋白BMF。相反，HDAC1过表达明显降低了BMF的表达。FK228诱导组蛋白H3和H4在BMF启动子区域发生乙酰化，但在其3‘端不发生乙酰化，提示组蛋白超乙酰化导致BMF转录激活。BMF转录本的敲除将细胞从FK228或CBHA诱导的细胞死亡、线粒体膜电位(Delta Psi M)的破坏和DNA片段化中拯救出来。总之，FK228和CBHA通过其启动子区域的组蛋白超乙酰化来激活BMF的转录，抑制这一作用会降低它们的促凋亡活性，从而突显BMF在HDAC抑制剂介导的细胞凋亡中的中心作用。
Histone deacetylase ( HDAC) inhibitors modify transcription of selected genes and eventually induce apoptosis. However, molecular mechanisms for their proapoptotic activity remain unclear. We here demonstrate that HDAC inhibitors FK228 and CBHA preferentially upregulated the BH3-only protein Bmf in a broad range of cancer cells. In contrast, HDAC1 overexpression distinctly reduced Bmf expression. FK228 induced histones H3 and H4 acetylation at Bmf promoter region, but not at its 3' region, suggesting that histone hyperacetylation causes Bmf transcriptional activation. Knockdown of Bmf transcripts rescued cells from FK228 or CBHA-induced cell death, disruption of mitochondrial membrane potential (Delta psi m) and DNA fragmentation. Taken together, FK228 and CBHA activate Bmf transcription by histone hyperacetylation at its promoter region, and inhibition of this action decreased their proapoptotic activity, thereby highlighting a central role of Bmf in HDAC inhibitor-mediated apoptosis.