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 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.
Authors
- Xiaofeng A. Su (ORCID: https://orcid.org/0000-0003-4960-6372)
- Sumaira Sardar
- Lakshmi Ravindranath
- Wei Yuan (ORCID: https://orcid.org/0000-0001-5694-8835)
- Nigel Brooks
- Karen E. Knudsen (ORCID: https://orcid.org/0000-0002-1301-890X)
- Denisa Bogdan (ORCID: https://orcid.org/0000-0002-3017-4832)
- Neil Pegg
- Lisa M. Butler (ORCID: https://orcid.org/0000-0003-2698-3220)
- Elise DeArment
- Ayesha A. Shafi (ORCID: https://orcid.org/0000-0003-0335-638X)
- Christopher McNair (ORCID: https://orcid.org/0000-0003-3204-8482)
- Adam Sharp (ORCID: https://orcid.org/0000-0002-3740-1612)
- Matthew J. Schiewer (ORCID: https://orcid.org/0000-0002-2325-4228)
- Johann Sebastian De Bono (ORCID: https://orcid.org/0000-0002-2034-595X)
- Natalie K. Ryan
- Saswati N. Chand (ORCID: https://orcid.org/0000-0001-5625-0517)
- Jon Welti
- Kris Frese
- Thomas Janas
- Liam A Knudsen
Institutions
- Henry M. Jackson Foundation (US)
- American Cancer Society (US)
- Institute of Cancer Research (GB)
- Uniformed Services University of the Health Sciences (US)
- Thomas Jefferson University (US)
- CellCentric (United Kingdom) (GB)
- Sidney Kimmel Cancer Center (US)
- Royal Marsden Hospital (GB)
- South Australian Health and Medical Research Institute (AU)
- Centre for Cancer Biology (AU)
- The University of Adelaide (AU)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Oncogene
- Published
- 2024-09-12
- DOI
- https://doi.org/10.1038/s41388-024-03148-4
- Citations
- 14
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 5.87
Funders
- Prostate Cancer Foundation
- Wellcome
- University of Pennsylvania
- Wellcome Trust
- Cancer Australia
- University of Adelaide
- Medical Research Council
- National Cancer Institute