Abstract B008: An epigenetic dependency on BRD8 in TP53-wild-type glioblastoma

Abstract Glioblastoma (GBM) is the most common and lethal primary brain malignancy in adults, with a median survival of 12–14 months and a 5-year survival rate of ∼6%. Despite decades of effort, patient outcomes have improved minimally, underscoring an urgent need for more effective and targeted therapies. We identified the bromodomain-containing chromatin regulator BRD8 as an essential dependency in TP53-wild-type (TP53WT) GBM, which comprises ∼71% of cases. BRD8 sustains malignancy by disabling p53-mediated tumor suppression through a previously unrecognized epigenetic mechanism: BRD8 reprograms the p53 regulatory network via the EP400 histone acetyltransferase complex and bromodomain-directed occupancy of the histone variant H2AZ at p53 target genes, enforcing a repressive chromatin state that blocks p53-dependent transactivation. Targeting BRD8 remodels chromatin by evicting H2AZ and increasing accessibility, and restores p53 binding and transcriptional activity. This reactivation of p53 restores gene expression, induces cell-cycle arrest, suppresses gliomagenesis, and prolongs survival in TP53WT GBM xenograft models. Our recent work further demonstrates that pharmacological targeting of BRD8 selectively restores p53 tumor-suppressive activity in TP53WT GBM cells, but not in non-malignant brain cells. Notably, BRD8 inhibition synergizes with multiple therapeutic pathways and enhances the efficacy of standard-of-care GBM treatments in patient-derived TP53WT GBM models. Together, these findings uncover a previously unappreciated epigenetic mechanism by which GBM cells evade p53-mediated tumor suppression, establish BRD8 as a tractable epigenetic vulnerability in TP53WT GBM, and nominate rational combination therapeutic strategies for GBM treatment. This work reveals new principles of chromatin-based tumor suppression and offers promising therapeutic avenues for this devastating disease. Citation Format: Xueqin Sherine Sun. An epigenetic dependency on BRD8 in TP53-wild-type glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B008.