Trichostatin A enhances acetylation as well as protein stability of ERalpha through induction of p300 protein.
Trichostatin A enhances acetylation as well as protein stability of ERalpha through induction of p300 protein.
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DOI：
10.1186/bcr2562
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Lee MO
中科院分区：
文献类型：
--
作者：
Kim SH;Kang HJ;Na H;Lee MO
曲古抑菌素A(TSA)是一种组蛋白脱乙酰酶(HDAC)抑制剂。TSA改变HDAC和组蛋白乙酰转移酶活性之间的平衡，这在染色质重塑和基因表达中是重要的。尽管先前的几项研究已经证明了TSA在雌激素受体α(ERα)调节中的作用，但TSA影响ERα活性的确切机制仍不清楚。使用Welfect-ex™Plus程序进行瞬时转染法。逆转录聚合酶链式反应(RT-PCR)检测其基因表达。免疫印迹和免疫沉淀法测定蛋白质的表达和相互作用。用寡聚糖胺™试剂法进行siRNA的转染。TSA处理后ERα乙酰化水平呈剂量依赖性增加。在TSA诱导ERα乙酰化的同时，ERα蛋白的稳定性增加。有趣的是，TSA还增加了p300蛋白的乙酰化和稳定性。P300过表达通过阻断泛素化诱导ERα乙酰化和稳定性。P300的乙酰化水平和ERα的蛋白水平均降低，提示p300介导了TSA诱导的ERα的稳定。我们报道，TSA通过调节p300的稳定性来增强ERα蛋白的乙酰化和稳定性。这些结果可能为HDAC抑制剂在人类乳腺癌治疗中的药理作用提供分子基础。
Trichostatin A (TSA) is a well-characterized histone deacetylase (HDAC) inhibitor. TSA modifies the balance between HDAC and histone acetyltransferase activities that is important in chromatin remodeling and gene expression. Although several previous studies have demonstrated the role of TSA in regulation of estrogen receptor alpha (ERα), the precise mechanism by which TSA affects ERα activity remains unclear. Transient transfection was performed using the Welfect-EX™Plus procedure. The mRNA expression was determined using RT-PCR. Protein expression and interaction were determined by western blotting and immunoprecipitation. The transfection of siRNAs was performed using the Oligofectamine™ reagent procedure. TSA treatment increased acetylation of ERα in a dose-dependent manner. The TSA-induced acetylation of ERα was accompanied by an increased stability of ERα protein. Interestingly, TSA also increased the acetylation and the stability of p300 protein. Overexpression of p300 induced acetylation and stability of ERα by blocking ubiquitination. Knockdown of p300 by RNA interference decreased acetylation as well as the protein level of ERα, indicating that p300 mediated the TSA-induced stabilization of ERα. We report that TSA enhanced acetylation as well as the stability of the ERα protein by modulating stability of p300. These results may provide the molecular basis for pharmacological functions of HDAC inhibitors in the treatment of human breast cancer.
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