Lorenza Pasqualini, Huajie Bu, Martin Puhr, Narisu Narisu, Johannes Rainer, Bettina Schlick, Georg Schäfer, Mihaela Angelova, Zlatko Trajanoski, Stefan T Börno, Michal R Schweiger, Christian Fuchsberger, Helmut Klocker

The normal prostate as well as early-stages and advanced prostate cancer (PCa) require a functional androgen receptor (AR) for growth and survival. The recent discovery of microRNAs (miRNAs) as novel effector molecules of AR disclosed the existence of an intricate network between AR, miRNAs and down-stream target genes. In this study DUCaP cells, characterized by high content of wild-type AR and robust AR transcriptional activity, were chosen as the main experimental model. By integrative analysis of ChIP-seq and microarray expression profiling data, miRNAs putatively bound and significantly regulated by AR were identified. A direct AR regulation of miR-22, miR-29a, and miR-17-92 cluster along with their host genes was confirmed. Interestingly, endogenous levels of miR-22 and miR-29a were found to be reduced in PCa cells expressing AR. In primary tumor samples, miR-22 and miR-29a were less abundant in the cancerous tissue compared to the benign counterpart. This specific expression pattern was associated with a differential DNA methylation of the genomic AR binding sites. The identification of LAMC1 and MCL1 as direct targets of miR-22 and miR-29a, respectively, suggested a tumor suppressive role of these miRNAs. Indeed, transfection of miRNA mimics in prostate cancer cells induced apoptosis and diminished cell migration and viability. Collectively, these data provide additional information regarding the complex regulatory machinery that guides miRNAs activity in PCa, highlighting an important contribution of miRNAs in the AR signaling.