| Title: |
AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer. |
| Authors: |
Sardar, S; McNair, CM; Ravindranath, L; Chand, SN; Yuan, W; Bogdan, D; Welti, J; Sharp, A; Ryan, NK; Knudsen, LA; Schiewer, MJ; DeArment, EG; Janas, T; Su, XA; Butler, LM; de Bono, JS; Frese, K; Brooks, N; Pegg, N; Knudsen, KE; Shafi, AA |
| Contributors: |
Yuan, Wei; Bogdan, Denisa Ioana; Sharp, Adam; De Bono, Johann |
| Publisher Information: |
SPRINGERNATURE |
| Publication Year: |
2024 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
Male; Humans; DNA Repair; Receptors; Androgen; Prostatic Neoplasms; Castration-Resistant; p300-CBP Transcription Factors; Cell Line; Tumor; Animals; Gene Expression Regulation; Neoplastic; Mice; DNA Damage; E1A-Associated p300 Protein |
| Subject Geographic: |
England |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; 3213; application/pdf |
| Language: |
English |
| ISSN: |
1476-5594; 0950-9232 |
| Relation: |
Oncogene, 2024, 43 (43), pp. 3197 - 3213; https://repository.icr.ac.uk/handle/internal/6500 |
| Availability: |
https://repository.icr.ac.uk/handle/internal/6500 |
| Rights: |
https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.6BB8BAB5 |
| Database: |
BASE |