Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.
Nucleic acids research. 2022 Dec 20 [Epub ahead of print]
Fan Zhang, Maitree Biswas, Shabnam Massah, Joseph Lee, Shreyas Lingadahalli, Samantha Wong, Christopher Wells, Jane Foo, Nabeel Khan, Helene Morin, Neetu Saxena, Sonia H Y Kung, Bei Sun, Ana Karla Parra Nuñez, Christophe Sanchez, Novia Chan, Lauren Ung, Umut Berkay Altıntaş, Jennifer M Bui, Yuzhuo Wang, Ladan Fazli, Htoo Zarni Oo, Paul S Rennie, Nathan A Lack, Artem Cherkasov, Martin E Gleave, Jörg Gsponer, Nada Lallous
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak St., Vancouver, BC V6H 3Z6, Canada., School of Medicine, Koç University, Rumelifeneri Yolu, Istanbul 34450, Turkey., Michael Smith Laboratories, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.