Previous studies have demonstrated an involvement of chromatin-remodelling SWI/SNF complexes in the development of prostate cancer, suggesting both tumor suppressor and oncogenic activities. SMARCD1/BAF60A, SMARCD2/BAF60B, and SMARCD3/BAF60C are mutually exclusive accessory subunits that confer functional specificity and are components of all known SWI/SNF subtypes. To assess the role of SWI/SNF in prostate tumorigenesis, we studied the functions and functional relations of the SMARCD family members. Performing RNA-seq in LnCAP cells grown in the presence or absence of dihydrotestosterone, we found that the SMARCD proteins are involved in the regulation of numerous hormone-dependent AR-driven genes. Moreover, we demonstrated that all SMARCD proteins can regulate AR-downstream targets in androgen-depleted cells, suggesting an involvement in the progression to castration-resistance. However, our approach also revealed a regulatory role for SMARCD proteins through antagonization of AR-signalling. We further demonstrated that the SMARCD proteins are involved in several important cellular processes such as the maintenance of cellular morphology and cytokinesis. Taken together, our findings suggest that the SMARCD proteins play an important, yet paradoxical, role in prostate carcinogenesis. Our approach also unmasked the complex interplay of paralogue SWI/SNF proteins that must be considered for the development of safe and efficient therapies targeting SWI/SNF.

Center for Cancer Research Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Core Facilities Medical University of Vienna 1090 Vienna Austria

Department of Analytical Chemistry Faculty of Chemistry University of Vienna 1010 Vienna Austria

Department of Laboratory Medicine Medical University of Vienna 1090 Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University 150 06 Prag Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Urology University of Texas Southwestern Dallas TX 75390 USA

Department of Urology Weill Cornell Medical College New York NY 10065 USA

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman 19328 Jordan

Joint Metabolome Facility University of Vienna and Medical University Vienna 1090 Vienna Austria

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