CBP/p300, a promising therapeutic target for prostate cancer
Hongtao Xu, Yifan Hou, Zhenhua Zhao, Jianhua Zhang, Pan Li, Yujia Cao, Xiaobo Nie, Junqing Hou
Abstract
Prostate cancer (PCa) remains the most prevalent malignancy among men, with the inevitable emergence of castration-resistant prostate cancer (CRPC) presenting the greatest challenge. Accumulating evidence has confirmed that the overexpression of cAMP response element-binding protein (CREB)-binding protein (CBP) and E1A-binding protein (p300), two highly homologous transcriptional coactivators, plays a crucial role in the development of PCa and its progression to CRPC, thereby making them prominent therapeutic targets for all types of PCa. In this review, we systematically discuss the structure and function of CBP/p300 and elucidate the detailed mechanisms by which CBP/p300 promote prostate carcinogenesis and development. Specifically, CBP/p300 facilitate prostate carcinogenesis by acetylating specific lysine residues on essential transcription factors involved in androgen receptor (AR) signaling, canonical Wnt signaling, p53 signaling, as well as other pathways such as PI3K/AKT and MAPK signaling. Additionally, they contribute to tumor immunosuppression and adaptive resistance to programmed death ligand 1 (PD-L1) blockade treatment by inducing the expression and secretion of the PD-L1 protein. Furthermore, we explore the latest advances in the use of various inhibitors targeting different domains of CBP/p300 and proteolysis-targeting chimeras (PROTAC) degraders in PCa. We propose that combing CBP/p300 inhibitors or degraders with current anti-PCa therapies, including androgen deprivation therapy (ADT), chemotherapy, and immunotherapy, holds potential to overcome the challenges in treating advanced PCa and improve clinical outcomes for all PCa patients.