Abstract Glioblastoma (GBM) remains the most aggressive and treatment-resistant primary brain tumor in adults, with median patient survival of only 12-15 months despite current standard-of-care therapies. To identify new therapeutic strategies, we investigated how chromatin remodeling regulates cell-state transitions in TP53 wild-type (TP53WT) GBM, which represents the majority of cases. We found that the chromatin regulator BRD8, a component of the EP400 complex, acts as a key suppressor of p53 activity. BRD8 maintains H2A.Z occupancy at p53 target loci to repress its tumor-suppressive paradigm. Depletion of BRD8 disrupts this interaction, increases chromatin accessibility, and reactivates p53-dependent transcriptional programs, resulting in a stable cell cycle arrest and a senescent phenotype accompanied by widespread transcriptomic reprogramming. Through small-molecule screening, we identified compounds that selectively impair the survival of BRD8-deficient cells, revealing specific vulnerabilities associated with this arrested state. We further discovered that the histone variant, macroH2A (mH2A), enforces the changes in chromatin accessibility and transcriptional output following BRD8 perturbation, functioning as epigenetic switches that stabilize this altered cell state. Together, these findings reveal a chromatin-based mechanism governing proliferative control in GBM and highlight actionable vulnerabilities that could be exploited through targeted pharmacologic intervention. Citation Format: Laurence Haddadin, Shuo Zhang, Mansi Solanki, Bin Lu, Xueqin (Sherine) Sun. Unraveling novel epigenetic therapies for the treatment of TP53WTglioblastoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3206.
Haddadin et al. (Fri,) studied this question.