title: Genome-wide impact of androgen receptor trapped clone-27 loss on androgen-regulated transcription in prostate cancer cells.
abstract: 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.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Nwachukwu
authors.forename: Paolo
authors.initials: P
authors.lastname: Mita
authors.forename: Rachel
authors.initials: R
authors.lastname: Ruoff
authors.forename: Susan
authors.initials: S
authors.lastname: Ha
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Huang
authors.forename: Samir S
authors.initials: SS
authors.lastname: Taneja
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: William L
authors.initials: WL
authors.lastname: Gerald
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
authors.forename: Susan K
authors.initials: SK
authors.lastname: Logan