Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer
Year: 2025
Type: article
Abstract: Prostate cancer is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CREB-binding protein (CBP) are key cofactors that activate enhancers through histone acetylation. Here we identify p300/CBP-mediated multisite histone H2B N-terminal acetylation (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancer. p300/CBP are essential for AR and ETS transcription factor ERG transcriptional activity, and their dual degradation eliminates H2BNTac and histone H3 lysine 27 acetylation at hyperactive enhancers, leading to stronger suppression of oncogenic transcription than targeting either paralog or bromodomain alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancer, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists and showed no evident toxicity. These findings position H2BNTac as an epigenetic marker of enhancer addiction and establish dual p300/CBP degradation as a promising therapeutic strategy for enhancer-driven cancers.
Source: Nature Genetics
Authors: Jie Luo, Zhixiang Chen, Yuanyuan Qiao, Jean Ching-Yi Tien, Eleanor Young, Rahul Mannan, Somnath Mahapatra, Rupam Bhattacharyya, Lanbo Xiao, Tongchen He, Sanjana Eyunni, Yuping Zhang, Yang Zheng, Fengyun Su, Xuhong Cao, Rui Wang, Yunhui Cheng, Rithvik Seri, James George, Miriam Shahine, Stephanie J. Miner, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Ulka Vaishampayan, Mi Wang, Shaomeng Wang, Abhijit Parolia, Arul M. Chinnaiyan
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: G134073379, G1404790370, G2323372041, SWI/SNF chromatin remodelers in tumor-associated antigen-specific CD8+ cytotoxic T cells, G2442261072, G3423956306, G3591966822, G394359466, G4797887072, G532147144, G6987519018, Orally active CBP/p300 degraders, G7227548224, Exploring Precision Oncology: From Gene Fusions to lncRNAs, G7640623676, G77804345, G855861786, G9000266437, University of Michigan Rogel Cancer Center Support Grant 2023-2028, Michigan Prostate SPORE 2025-2030, Michigan-VUMC Biomarker Characterization Center
OpenAlex ID: W4414777592