Genome-wide impact of androgen receptor trapped clone-27 loss on androgen-regulated transcription in prostate cancer cells.
Genome-wide impact of androgen receptor trapped clone-27 loss on androgen-regulated transcription in prostate cancer cells.
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DOI：
10.1158/0008-5472.can-08-3738
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Logan SK
中科院分区：
文献类型：
--
作者：
Nwachukwu JC;Mita P;Ruoff R;Ha S;Wang Q;Huang SJ;Taneja SS;Brown M;Gerald WL;Garabedian MJ;Logan SK
The Androgen Receptor (AR) directs diverse biological processes through interaction with coregulators such as Androgen Receptor Trapped clone-27 (ART-27). Our results demonstrate that ART-27 is recruited to AR-binding sites by ChIP analysis. In addition, the impact of ART-27 on genome wide transcription was examined. The studies indicate that loss of ART-27 enhances expression of many androgen-regulated genes, suggesting that ART-27 inhibits gene expression. Surprisingly, classes of genes that are upregulated upon ART-27 depletion include regulators of DNA damage checkpoint and cell cycle progression, suggesting that ART-27 functions to keep expression levels of these genes low. Consistent with this idea, stable reduction of ART-27 by shRNA enhances LNCaP cell proliferation compared to control cells. The impact of ART-27 loss was also examined in response to the antiandrogen, bicalutamide. Unexpectedly, cells treated with ART-27 siRNA no longer exhibited gene repression in response to bicalutamide. To examine ART-27 loss in prostate cancer progression, immunohistochemistry was conducted on a tissue array containing samples from primary tumors of individuals who were clinically followed and later shown to have either recurrent or non-recurrent disease. Comparison of ART-27 and AR staining indicated that nuclear ART-27 expression was lost in the majority of AR-positive recurrent prostate cancers. Our studies demonstrate that reduction of ART-27 protein levels in prostate cancer may facilitate antiandrogen resistant disease.
