AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer

Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance th...

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Bibliographic Details
Published in:Oncogene 2024-10, Vol.43 (43), p.3197-3213
Main Authors: Sardar, Sumaira, McNair, Christopher M., Ravindranath, Lakshmi, Chand, Saswati N., Yuan, Wei, Bogdan, Denisa, Welti, Jon, Sharp, Adam, Ryan, Natalie K., Knudsen, Liam A., Schiewer, Matthew J., DeArment, Elise G., Janas, Thomas, Su, Xiaofeng A., Butler, Lisa M., de Bono, Johann S., Frese, Kris, Brooks, Nigel, Pegg, Neil, Knudsen, Karen E., Shafi, Ayesha A.
Format: Article
Language:English
Subjects:
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631/67/589/466
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Androgen receptors
Apoptosis
Castration
Cell Biology
DNA damage
DNA repair
Histones
Homologous recombination
Human Genetics
Internal Medicine
Medicine
Medicine & Public Health
Metastases
Oncology
Prostate cancer
Therapeutic targets
Transcriptomes
Tumorigenesis
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Summary:Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-024-03148-4