Enzalutamide is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the disease almost always develops resistance. Given that many enzalutamide-resistant tumors lack specific somatic mutations, there is strong evidence that epigenetic factors can cause enzalutamide resistance. To explore how resistance arises, we systematically test all epigenetic modifiers in several models of castration-resistant and enzalutamide-resistant prostate cancer with a custom epigenetic CRISPR library. From this, we identify and validate SMARCC2, a core component of the SWI/SNF complex, that is selectivity essential in enzalutamide-resistant models. We show that the chromatin occupancy of SMARCC2 and BRG1 is expanded in enzalutamide resistance at regions that overlap with CRPC-associated transcription factors that are accessible in CRPC clinical samples. Overall, our study reveals a regulatory role for SMARCC2 in enzalutamide-resistant prostate cancer and supports the feasibility of targeting the SWI/SNF complex in late-stage PCa.
Communications biology. 2025 Feb 04*** epublish ***
Bengul Gokbayrak, Umut Berkay Altintas, Shreyas Lingadahalli, Tunc Morova, Chia-Chi Flora Huang, Betul Ersoy Fazlioglu, Ivan Pak Lok Yu, Batuhan M Kalkan, Paloma Cejas, Sonia H Y Kung, Ladan Fazli, Akane Kawamura, Henry W Long, Ceyda Acilan, Tamer T Onder, Tugba Bagci-Onder, James T Lynch, Nathan A Lack
Koc University Research Centre for Translational Medicine (KUTTAM), Istanbul, Turkey., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada., Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, USA., Chemistry - School of Natural and Environmental Sciences, Newcastle University, Newcastle, UK., Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK., Koc University Research Centre for Translational Medicine (KUTTAM), Istanbul, Turkey. .