Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis.
Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis.
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DOI：
10.1158/1535-7163.mct-08-1166
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发表时间：
2009-05
影响因子：
5.7
通讯作者：
Lee AS
中科院分区：
文献类型：
--
作者：
Baumeister P;Dong D;Fu Y;Lee AS
组蛋白去乙酰化酶（Histone deacetylase， HDAC）抑制剂正在成为治疗癌症的有效疗法，HDAC在调控启动子中的作用正在迅速扩大。GRP78/BiP是一种具有抗凋亡特性的应激诱导内质网（ER）伴侣。我们在此提出了组蛋白去乙酰化酶1 （HDAC1）抑制Grp78启动子的机制。我们的研究表明，HDAC抑制剂能够特异性诱导GRP78，且诱导水平被内质网应激放大。通过突变分析，我们已经确定了最小Grp78启动子和负责hdac介导的抑制的特定元件。我们发现HDAC1参与Grp78启动子的负调控，不仅通过其在HDAC抑制剂trichostatin A和MS-275存在时的诱导，还通过外源性过表达和特异性HDAC的siRNA敲低。我们提出了染色质免疫沉淀分析的结果，揭示了在内质网应激之前而不是之后HDAC1与Grp78启动子的结合。此外，GRP78的过表达使癌细胞对HDAC抑制剂诱导的凋亡产生抗性，相反，GRP78的抑制使其对HDAC抑制剂敏感。这些结果将HDAC抑制剂定义为上调GRP78而不同时诱导内质网或热休克应激反应的新型药物，抑制肿瘤中的GRP78可能提供一种新的辅助选择，以增强利用这些化合物的抗癌治疗。
Histone deacetylase (HDAC) inhibitors are emerging as effective therapies in the treatment of cancer, and the role of HDACs in the regulation of promoters is rapidly expanding. GRP78/BiP is a stress inducible endoplasmic reticulum (ER) chaperone with anti-apoptotic properties. We present here the mechanism for repression of the Grp78 promoter by histone deacetylase 1 (HDAC1). Our studies reveal that HDAC inhibitors specifically induce GRP78, and the induction level is amplified by ER stress. Through mutational analysis, we have identified the minimal Grp78 promoter and specific elements responsible for HDAC-mediated repression. We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275, but also by exogenous overexpression and siRNA knockdown of specific HDACs. We present the results of chromatin immunoprecipitation analysis that reveals the binding of HDAC1 to the Grp78 promoter before but not after ER stress. Furthermore, overexpression of GRP78 confers resistance to HDAC inhibitor induced apoptosis in cancer cells and, conversely, suppression of GRP78 sensitizes them to HDAC inhibitor. These results define HDAC inhibitors as new agents that upregulate GRP78 without concomitantly inducing the ER or heat shock stress response, and suppression of GRP78 in tumors may provide a novel, adjunctive option to enhance anti-cancer therapies that utilize these compounds.