Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors
Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression. Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids, we identified bromodomain protein BRD4 as a crucial player. Integrated ChIP-seq and RNA-seq analysis of tumors...
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Elsevier
2025-03-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525000127 |
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| author | Xiong Zhang Yatian Yang Hongye Zou Yang Yang Xingling Zheng Eva Corey Amina Zoubeidi Nicolas Mitsiades Ai-Ming Yu Yuanpei Li Hong-Wu Chen |
| author_facet | Xiong Zhang Yatian Yang Hongye Zou Yang Yang Xingling Zheng Eva Corey Amina Zoubeidi Nicolas Mitsiades Ai-Ming Yu Yuanpei Li Hong-Wu Chen |
| author_sort | Xiong Zhang |
| collection | DOAJ |
| description | Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression. Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids, we identified bromodomain protein BRD4 as a crucial player. Integrated ChIP-seq and RNA-seq analysis of tumors revealed, for the first time, that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis, axonogenesis, EMT and stem cells and key drivers such as POU3F2 (BRN2), ASCL1/2, NeuroD1, SOX2/9, RUNX1/2 and DLL3. Interestingly, BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1. Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases. |
| format | Article |
| id | doaj-art-ab2a2cd9d8c242bd917387d740eb1575 |
| institution | OA Journals |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-ab2a2cd9d8c242bd917387d740eb15752025-08-20T02:25:35ZengElsevierActa Pharmaceutica Sinica B2211-38352025-03-011531415142910.1016/j.apsb.2025.01.007Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitorsXiong Zhang0Yatian Yang1Hongye Zou2Yang Yang3Xingling Zheng4Eva Corey5Amina Zoubeidi6Nicolas Mitsiades7Ai-Ming Yu8Yuanpei Li9Hong-Wu Chen10Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USADepartment of Urology, University of Washington, Seattle, DC 98915, USADepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z1M9, CanadaDepartment of Internal Medicine, Division of Hematology and Oncology, School of Medicine, University of California Davis, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA; Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA; VA Northern California Health Care System-Mather, Mather, CA 95655, USA; Corresponding author.Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression. Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids, we identified bromodomain protein BRD4 as a crucial player. Integrated ChIP-seq and RNA-seq analysis of tumors revealed, for the first time, that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis, axonogenesis, EMT and stem cells and key drivers such as POU3F2 (BRN2), ASCL1/2, NeuroD1, SOX2/9, RUNX1/2 and DLL3. Interestingly, BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1. Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.http://www.sciencedirect.com/science/article/pii/S2211383525000127Tumor lineage plasticityBRD4NeurogenesisAZD5153FOXA1ChIP-seq |
| spellingShingle | Xiong Zhang Yatian Yang Hongye Zou Yang Yang Xingling Zheng Eva Corey Amina Zoubeidi Nicolas Mitsiades Ai-Ming Yu Yuanpei Li Hong-Wu Chen Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors Acta Pharmaceutica Sinica B Tumor lineage plasticity BRD4 Neurogenesis AZD5153 FOXA1 ChIP-seq |
| title | Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors |
| title_full | Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors |
| title_fullStr | Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors |
| title_full_unstemmed | Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors |
| title_short | Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors |
| title_sort | effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by brd4 inhibitors |
| topic | Tumor lineage plasticity BRD4 Neurogenesis AZD5153 FOXA1 ChIP-seq |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525000127 |
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