Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer
Abstract 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 so...
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Nature Portfolio
2025-02-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07413-w |
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| author | 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 |
| author_facet | 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 |
| author_sort | Bengul Gokbayrak |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-9273142519234b4fb532854e1afe6cb3 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-9273142519234b4fb532854e1afe6cb32025-02-09T12:50:52ZengNature PortfolioCommunications Biology2399-36422025-02-018111210.1038/s42003-024-07413-wIdentification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancerBengul Gokbayrak0Umut Berkay Altintas1Shreyas Lingadahalli2Tunc Morova3Chia-Chi Flora Huang4Betul Ersoy Fazlioglu5Ivan Pak Lok Yu6Batuhan M. Kalkan7Paloma Cejas8Sonia H. Y. Kung9Ladan Fazli10Akane Kawamura11Henry W. Long12Ceyda Acilan13Tamer T. Onder14Tugba Bagci-Onder15James T. Lynch16Nathan A. Lack17Koc University Research Centre for Translational Medicine (KUTTAM)Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaVancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaVancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaVancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaKoc University Research Centre for Translational Medicine (KUTTAM)Vancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaKoc University Research Centre for Translational Medicine (KUTTAM)Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical SchoolVancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaVancouver Prostate Centre, Department of Urologic Sciences, University of British ColumbiaChemistry - School of Natural and Environmental Sciences, Newcastle UniversityDepartment of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical SchoolKoc University Research Centre for Translational Medicine (KUTTAM)Koc University Research Centre for Translational Medicine (KUTTAM)Koc University Research Centre for Translational Medicine (KUTTAM)Research and Early Development, Oncology R&D, AstraZenecaKoc University Research Centre for Translational Medicine (KUTTAM)Abstract 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.https://doi.org/10.1038/s42003-024-07413-w |
| spellingShingle | 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 Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer Communications Biology |
| title | Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer |
| title_full | Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer |
| title_fullStr | Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer |
| title_full_unstemmed | Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer |
| title_short | Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer |
| title_sort | identification of selective swi snf dependencies in enzalutamide resistant prostate cancer |
| url | https://doi.org/10.1038/s42003-024-07413-w |
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