Researchers at the University of Michigan Health Rogel Cancer Center have identified a histone modification that plays a key role in prostate cancer progression and developed a compound that selectively disrupts the proteins responsible for it. The findings, published in Nature Genetics, describe how histone H2B N-terminal acetylation (H2BNTac) acts as a defining feature of tumor-promoting enhancers.
The study, led by Arul Chinnaiyan, S.P. Hicks Endowed Professor of Pathology and director of the Michigan Center for Translational Pathology, shows that the enzymes p300 and CBP, which catalyze the addition of H2BNTac, are elevated in prostate cancer tissue. These proteins, along with the androgen receptor (AR), activate enhancers that drive cancer growth. “This study began as a way to understand chromatin associated with prostate cancer more thoroughly. But we found that if you degrade p300 and CBP, levels of H2BNTac are depleted at AR enhancer sites,” said Chinnaiyan.
To explore this mechanism therapeutically, Chinnaiyan collaborated with Shaomeng Wang, director of the Michigan Center for Therapeutic Innovation, to develop CBPD-409, a selective degrader of p300 and CBP. The oral compound removes H2BNTac and suppresses AR-driven oncogenic activity. “CBPD-409 rapidly and selectively erases H2BNTac, but remains untouched by bromodomain inhibitors, another class of drugs targeting p300 and CBP that do not fully extinguish their activity,” Chinnaiyan noted.
In preclinical models, cells with high H2BNTac levels were more responsive to the drug, and CBPD-409 induced tumor regression in castration-resistant prostate cancer while showing good tolerability in mice. Wang said, “These promising preclinical findings support the development of a selective p300/CBP degrader for the treatment of castration-resistant prostate cancer in the clinic.”
Publication Details
Luo, J., Chen, Z., Qiao, Y. et al. Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer. Nat Genet 57, 2468–2481 (2025). https://doi.org/10.1038/s41588-025-02336-6
The study, led by Arul Chinnaiyan, S.P. Hicks Endowed Professor of Pathology and director of the Michigan Center for Translational Pathology, shows that the enzymes p300 and CBP, which catalyze the addition of H2BNTac, are elevated in prostate cancer tissue. These proteins, along with the androgen receptor (AR), activate enhancers that drive cancer growth. “This study began as a way to understand chromatin associated with prostate cancer more thoroughly. But we found that if you degrade p300 and CBP, levels of H2BNTac are depleted at AR enhancer sites,” said Chinnaiyan.
To explore this mechanism therapeutically, Chinnaiyan collaborated with Shaomeng Wang, director of the Michigan Center for Therapeutic Innovation, to develop CBPD-409, a selective degrader of p300 and CBP. The oral compound removes H2BNTac and suppresses AR-driven oncogenic activity. “CBPD-409 rapidly and selectively erases H2BNTac, but remains untouched by bromodomain inhibitors, another class of drugs targeting p300 and CBP that do not fully extinguish their activity,” Chinnaiyan noted.
In preclinical models, cells with high H2BNTac levels were more responsive to the drug, and CBPD-409 induced tumor regression in castration-resistant prostate cancer while showing good tolerability in mice. Wang said, “These promising preclinical findings support the development of a selective p300/CBP degrader for the treatment of castration-resistant prostate cancer in the clinic.”
Publication Details
Luo, J., Chen, Z., Qiao, Y. et al. Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer. Nat Genet 57, 2468–2481 (2025). https://doi.org/10.1038/s41588-025-02336-6