Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA.
Oncogene. 2024 Oct;43(43):3197-3213. doi: 10.1038/s41388-024-03148-4. Epub 2024 Sep 13.
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.
去势抵抗性前列腺癌（CRPC）仍然是一种无法治愈的疾病阶段，治疗选择效果不佳。在这里，雄激素受体（AR）共激活剂 CBP/p300 被鉴定为 DNA 损伤修复（DDR）的关键介质，可能增强 CRPC 的治疗靶向。主要发现表明，CBP/p300 的表达随着疾病的进展而增加，并选择转移性疾病的预后不良。CBP/p300 的溴结构域抑制增强了对标准治疗药物的反应。在 CRPC 中的功能研究、CBP/p300 染色质图谱和转录组学表明，CBP/p300 调节 DDR。进一步的机制研究表明，通过治疗靶向和基因组敲低来减弱 CBP/p300，可减少体外、体内和人类前列腺癌（PCa）肿瘤的同源重组（HR）因子。同样，人前列腺组织中的 CBP/p300 表达与 HR 因子相关。最后，靶向 CBP/p300 会影响 HR 介导的修复和患者预后。总之，这些研究将 CBP/p300 确定为 PCa 肿瘤发生的驱动因素，并为通过 CBP/p300 抑制优化晚期 PCa 的治疗策略奠定了基础，可能与 AR 靶向和 DDR 治疗联合使用。
