Abstract
Androgen receptor (AR), a ligand-dependent transcription factor, plays a critical role in prostate cancer onset and progression, and its transcriptional function is mediated largely by distinct nuclear receptor co-regulators. Here, we show that cell cycle and apoptosis regulator 1 (CCAR1) functions as an AR co-activator. CCAR1 interacted with and enhanced the transcriptional activity of AR. Depletion of CCAR1 caused reduction in androgen-dependent expression of a subset of AR target genes. We further showed that CCAR1 is required for recruitment of AR, MED1 and RNA polymerase II to the enhancers of AR target genes and for androgen-induced long-range prostate specific antigen enhancer–promoter interaction. The molecular mechanism underlying CCAR1 function in AR-mediated transcription involves CCAR1-mediated enhanced recruitment of GATA2, a pioneer factor for AR, to AR-binding sites. CCAR1 stabilized the interaction between AR and GATA2 by interacting directly with both proteins, thereby facilitating AR and GATA2 occupancy on the enhancers. Furthermore, CCAR1 depletion inhibited the growth, migration, invasion of prostate cancer cells and reduced the tumorigenicity of prostate cancer cells in vivo. Our results firmly established CCAR1 as an AR co-activator that plays a key role in AR transcription complex assembly and has an important physiological role in androgen signaling and prostate tumorigenesis.
Highlights
Androgen receptor (AR), a member of the nuclear receptor (NR) superfamily, functions as a ligand-dependent transcription factor that plays a key role in the growth and maintenance of the normal prostate and the onset and progression of prostate cancer [1,2]
Given our findings that cycle and apoptosis regulator 1 (CCAR1) interacts with members of the NR family [8], such as estrogen receptor a (ERa) and glucocorticoid receptor (GR), we first examined the association between endogenous CCAR1 and AR in AR-positive LNCaP prostate cancer cells by coimmunoprecipitation (CoIP) assays
In vitro glutathione-S-transferase (GST) pull-down assays confirmed the interaction between CCAR1 and AR (Supplementary Figure S1B) and showed that CCAR1 interacts with the C-terminal region of AR in a hormone-independent manner (Supplementary Figure S1C, D and E), suggesting that CCAR1 interacts directly with AR
Summary
Androgen receptor (AR), a member of the nuclear receptor (NR) superfamily, functions as a ligand-dependent transcription factor that plays a key role in the growth and maintenance of the normal prostate and the onset and progression of prostate cancer [1,2]. AR binds to androgen response elements (AREs) in the enhancer and promoter regions of target genes. Recent genome-wide ChIP-on-chip studies have shown that motifs for pioneer factors (e.g. FoxA1, GATA2 and Oct1) are significantly enriched within the AR-binding regions, compared with genomic background [5,6]. The pioneer factors FoxA1 and GATA2 are recruited to a significant portion of ARbinding sites in prostate cancer cells, facilitating AR binding to AREs by interacting directly with AR and enhancing AR-mediated transcription. Once bound to AREs, AR regulates the expression of a variety of target genes through the recruitment of co-regulators
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