p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer

Abstract

Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation. Here, we demonstrate that p300/CBP are determinant cofactors of the active AR enhanceosome in prostate cancer. Histone H2B N-terminus multisite lysine acetylation (H2BNTac), which was exclusively reliant on p300/CBP catalytic function, marked active enhancers and was notably elevated in prostate cancer lesions relative to the adjacent benign epithelia. Degradation of p300/CBP rapidly depleted acetylation marks associated with the active AR enhanceosome, which was only partially phenocopied by inhibition of their reader bromodomains. Notably, H2BNTac was effectively abrogated only upon p300/CBP degradation, which led to a stronger suppression of p300/CBP-dependent oncogenic gene programs relative to bromodomain inhibition. In vivo experiments using a novel, orally active p300/CBP proteolysis targeting chimera (PROTAC) degrader (CBPD-409) showed that p300/CBP degradation potently inhibited tumor growth in preclinical models of castration-resistant prostate cancer and synergized with AR antagonists. While mouse p300/CBP orthologs were effectively degraded in host tissues, prolonged treatment with the PROTAC degrader was well tolerated with no significant signs of toxicity. Taken together, our study highlights the pivotal role of p300/CBP in maintaining the active AR enhanceosome and demonstrates how target degradation may have functionally distinct effects relative to target inhibition, thus supporting the development of p300/CBP degraders for the treatment of advanced prostate cancer.

Paralogue-Selective Degradation of the Lysine Acetyltransferase EP300

“…Interestingly, a recent study reported that dual EP300/CREBBP degraders do not cause weight loss in mice. 38 This implies either that dual loss of EP300/CREBBP catalytic activity is more well-tolerated than expected, or that the unique pharmacology of bifunctional molecules may spare EP300/CREBBP in settings where it is essential. Related to this, VHL-linked degraders have shown the capacity to mitigate thrombocytopenia caused by their parent inhibitor compounds in platelet models.…”

“…In this latter scenario, MC-1 may be deployed as an augmented HAT inhibitor with an additional capability to degrade EP300. Interestingly, a recent study reported that dual EP300/CREBBP degraders do not cause weight loss in mice . This implies either that dual loss of EP300/CREBBP catalytic activity is more well-tolerated than expected, or that the unique pharmacology of bifunctional molecules may spare EP300/CREBBP in settings where it is essential.…”

Selective p300 degradation via peptide PROTAC: a new therapeutic strategy for advanced prostate cancers

“…In prostate cancer, the transcriptional activity of the androgen receptor (AR) relies on p300/CBP, which catalyzes AR acetylation to enhance coactivator binding, and deposits histone acetylation at target enhancers to program a cancer-specific AR-dependent transcriptome. 1 , 2 , 3 Additionally, the expression of AR and various tumor-promoting factors, such as c-Myc and FOXA1, also depends on p300 and super enhancer activities. 3 , 4 , 5 , 6 These essential tumorigenic roles of p300/CBP make them promising therapeutic targets for prostate cancer treatment.…”

“… 1 , 2 , 3 Additionally, the expression of AR and various tumor-promoting factors, such as c-Myc and FOXA1, also depends on p300 and super enhancer activities. 3 , 4 , 5 , 6 These essential tumorigenic roles of p300/CBP make them promising therapeutic targets for prostate cancer treatment.…”

“…Despite these similarities, functional evidence and chromatin binding analyses indicate distinct roles for p300 and CBP in various cell types, including prostate cancer. 3 , 4 , 7 Given that conventional inhibitors targeting either the HAT or BRD domain incompletely hinder the oncogenic activity of p300/CBP, targeted protein degradation (TPD) via proteolysis-targeting chimera (PROTAC) technology has emerged as a promising approach in recent p300/CBP drug discovery. 8 Several small-molecule-based p300/CBP PROTACs have been reported in recent years.…”