Abstract PO048: Inhibition of P300 histone acetyltransferase activity rescues invasive phenotypes of ARID1A-deficient endometrial epithelium

Abstract Invasion is a hallmark feature of endometrial pathologies, including myometrial invasion of endometrial cancer and invasion of distal sites during endometriosis. Mutations in the chromatin remodeling protein ARID1A have been observed at high rates in endometrial cancer and endometriosis. ARID1A loss, in combination with phosphoinositide 3-kinase (PI3K) pathway activation, has been shown to induce invasion phenotypes in the endometrial epithelium. Using bioinformatic approaches, we identified histone acetyltransferase (HAT) protein P300 as potential co-regulator of ARID1A-deficient gene expression programs. Knockdown of P300 prevented invasive phenotypes in a genetically engineered mouse model and human endometrial epithelial cells through induction of apoptosis, indicating a synthetic-lethal relationship between ARID1A and P300 in the endometrial epithelium. Using the novel HAT inhibitor, A-485, we identified P300 HAT activity as the mechanism by which P300 promotes invasive phenotypes. A-485 treatment rescued invasion in vitro at concentrations which had no effect on cell viability in adherent culture, but induced anoikis in suspension culture. Using an RNA-seq approach, we identified cell adhesion and migration pathways as being regulated by ARID1A knockdown and P300 co-knockdown or A-485 co-treatment. Among genes in these pathways, we identified SERPINE1 as an essential component of P300-dependent invasive processes. SERPINE1 is overexpressed following ARID1A loss in mouse and human models, and SERPINE1 knockdown rescued invasive phenotypes following ARID1A loss. By chromatin immunoprecipitation, we identified a role for P300-dependent acetylation of histone 3 lysine 27 (H3K27ac) at the SERPINE1 super-enhancer. The novel P300 bromodomain inhibitor CCS1477 also rescues invasion and SERPINE1 expression following ARID1A loss, suggesting a role for bromodomain inhibition as a modulator of P300 H3K27ac deposition. These studies suggest the therapeutic utility of P300 inhibition to induce anoikis in mutant endometrium which has detached from the basement membrane, thereby preventing invasion. Citation Format: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler. Inhibition of P300 histone acetyltransferase activity rescues invasive phenotypes of ARID1A-deficient endometrial epithelium [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO048.