一种依赖组蛋白去乙酰化的机制对前列腺癌细胞中间隙连接基因cx43进行转录抑制。
A histone deacetylation-dependent mechanism for transcriptional repression of the gap junction gene cx43 in prostate cancer cells.
作者信息
Hernandez Maite, Shao Qing, Yang Xiang-Jiao, Luh Shi-Ping, Kandouz Mustapha, Batist Gerald, Laird Dale W, Alaoui-Jamali Moulay A
机构信息
Departments of Medicine, Oncology, and Pharmacology and Therapeutics, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, 3755 Chemin de la Cote Ste-Catherine, Montreal, Quebec, Canada.
出版信息
Prostate. 2006 Aug 1;66(11):1151-61. doi: 10.1002/pros.20451.
BACKGROUND
The connexin 43 gene (cx43, GJA1) mediates gap junctional intercellular communication (GJIC), which regulates tissue homeostasis. cx43 is frequently downregulated in prostate cancer. We investigated the role of a histone deacetylase (HDAC)-dependent mechanism in the transcriptional repression of cx43 in a panel of prostate cancer cells.
METHODS
The impact of Trichostatin A (TSA), an inhibitor of HDAC, on exogenous and endogenous cx43 gene transcription was examined by the luciferase assay, Northern blot, nuclear run-on, Western blot, and chromatin immunoprecipitation assays.
RESULTS
Trichostatin A induces transcription of cx43 gene and GJIC. The co-activator p300/CBP synergizes with TSA for cx43 promoter activation. We identified a promoter region where cooperation between Ap1 and Sp1 elements was essential for TSA-induced cx43 transcription. TSA increased the level of hyperacetylated histones bound to cx43 promoter.
CONCLUSION
Our results highlight the potential utility of inhibitors of HDAC to restore cx43 gene expression in prostate cancer.
背景
连接蛋白43基因（cx43，GJA1）介导间隙连接细胞间通讯（GJIC），其调节组织稳态。cx43在前列腺癌中经常下调。我们在一组前列腺癌细胞中研究了组蛋白去乙酰化酶（HDAC）依赖性机制在cx43转录抑制中的作用。
方法
通过荧光素酶测定、Northern印迹、核转录、Western印迹和染色质免疫沉淀测定，检测HDAC抑制剂曲古抑菌素A（TSA）对外源和内源性cx43基因转录的影响。
结果
曲古抑菌素A诱导cx43基因转录和GJIC；共激活因子p300/CBP与TSA协同作用激活cx43启动子。我们鉴定出一个启动子区域，其中Ap1和Sp1元件之间的协同作用对于TSA诱导的cx43转录至关重要。TSA增加了与cx43启动子结合的高乙酰化组蛋白水平。
结论
我们的结果突出了HDAC抑制剂在恢复前列腺癌中cx43基因表达方面的潜在效用。
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