Abstract 4768: From peptide screens to biological insights, FOXO4 and the PBAF complex

Abstract Bromodomains are ubiquitous among chromatin regulators, and while they are potentially exciting therapeutic targets for cancer, the specific functions of many of them remain unknown. In a high-throughput peptide screen for potential bromodomain binding partners, acetylated peptides of transcription factors FOXO1/3/4 emerged as significant binders to the polybromo protein PBRM1, a subunit of the SWI/SNF chromatin remodeler PBAF. FOXOs are of particular interest because they are well-conserved mediators of stress adaptation in cells and are regulated by several PTMs. Under oxidative stress, FOXOs are acetylated and translocate to the nucleus, where PBRM1, within PBAF, resides. We sought to characterize the interaction between acetylated FOXOs and PBRM1 and their potential cooperation in stress responses. (1) We validated the interaction by Isothermal titration calorimetry (ITC) and found acetylated FOXO peptides bind to PBRM1 bromodomains with affinities comparable to peptides including the preferred histone modification, H3K14ac. (2) Using purified, site-specifically acetylated FOXO4 proteins as bait, we purified interactors for mass spec analysis, finding that FOXO4 acetylated at K189 interacts with PBAF components. (3) We employed genomic profiling assays ATAC-seq, CUT Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4768.