This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-3738v1 69/7/3140    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nwachukwu, J. C. Articles by Logan, S. K. Search for Related Content PubMed PubMed Citation Articles by Nwachukwu, J. C. Articles by Logan, S. K.

Genome-Wide Impact of Androgen Receptor Trapped clone-27 Loss on Androgen-Regulated Transcription in Prostate Cancer Cells

Departments of ¹ Pharmacology, ² Microbiology, and ³ Urology, and NYU Cancer Institute, New York University School of Medicine, and ⁴ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; ⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; and ⁶ Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Susan K. Logan, Departments of Urology and Pharmacology, New York University School of Medicine, 550 First Avenue, MSB424, New York, NY 10016. Phone: 212-263-2921; Fax: 212-263-7133; E-mail: susan.logan{at}nyumc.org.

Key Words: ART-27 • UXT • AR • cofactor • coregulator • prostate cancer • hormone refractory • androgen independent • microarray

The androgen receptor (AR) directs diverse biological processes through interaction with coregulators such as AR trapped clone-27 (ART-27). Our results show that ART-27 is recruited to AR-binding sites by chromatin immunoprecipitation analysis. In addition, the effect 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 up-regulated 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 short-hairpin RNA enhances LNCaP cell proliferation compared with control cells. The effect 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 nonrecurrent 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 show that reduction of ART-27 protein levels in prostate cancer may facilitate antiandrogen-resistant disease. [Cancer Res 2009;69(7):3140–7]