Abstract 3549: miRNAs and androgen receptor interplay in prostate cancer

Abstract

Abstract Background In the treatment of advanced prostate cancer (PCa) a common strategy is to interfere with androgen receptor (AR) transcriptional activity by means of androgen deprivation. Despite an initial good response, the majority of tumors eventually progress to an androgen-independent phenotype, known as castrate-resistant prostate cancer (CRPC) which retains enhanced AR signaling and for which effective long-term treatment is currently not available. The discovery of miRNAs as novel members of the AR transcriptome disclosed the existence of an intricate network between AR, miRNAs and down-stream target genes that needs to be further investigated. Materials and Methods A list of potential AR regulated miRNAs and/or their host genes (HGs) was generated through microarray-based expression profiling and chromatin-immunoprecipitation coupled with deep sequencing (ChIP-seq) in prostate cancer cells. AR binding sites in the candidate miRNAs and HGs were verified after 1 h of androgen stimulation using androgen receptor chromatin immunoprecipitation followed by PCR detection of the binding sites. Real-time PCR was performed to analyze the changes of expression after 24 h and 48 h of androgen treatment. As experimental models, AR positive DUCaP and LNCaP cell lines were chosen. Results Overall, 29 miRNAs and/or miRNA-HGs were detected to be significantly regulated upon 8 h and 24 h of androgen treatment and to harbor single or multiple putative AR binding sites. A direct association of AR with miR22, miR29a and the miR17-92 cluster was validated along with their regulation after androgen stimulation. For the miR17-92 cluster and miR22, it was additionally confirmed that the expression of the HGs and the corresponding resident miRNAs are affected similarly by androgen exposure. Interestingly, the basal levels of the miRNAs under study appear reduced in AR positive cell lines when compared with AR negative ones. Conclusions The AR transcriptome includes specific miRNAs whose aberrant expression is associated with well known pro- or anti-oncogenic effects. Further information on the complex regulatory machinery that guides miRNAs activity and role in prostate cancer cells are provided with this work, highlighting the importance of the interplay between miRNAs and AR. Indeed, the selected miRNAs are differentially expressed in various prostate cancer cell lines depending on AR presence or absence and are also regulated upon androgen stimulation. Hence, this class of miRNAs may represent new promising biomarkers for prostate cancer or novel potential therapeutic targets for treatment of castrate-resistant prostate cancer. Supported by the PhD Program MCBO of FWF Citation Format: Lorenza Pasqualini, Huajie Bu, Narisu Narisu, Johannes Rainer, Michal R. Schweiger, Peter S. Chines, Christian Fuchsberger, Helmut Klocker. miRNAs and androgen receptor interplay in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3549. doi:10.1158/1538-7445.AM2014-3549