Abstract 7190: Targeting KDM6A and KDM6B histone demethylases to exploit epigenetic vulnerabilities in IDH mutant gliomas

Abstract Gliomas, accounting for 80% of malignant brain tumors, are notably aggressive and may harbor IDH1 mutations, leading to 2-hydroxyglutarate accumulation. This accumulation inhibits DNA and histone demethylases, creating a hypermethylated phenotype. Therefore, understanding and exploiting epigenetic vulnerabilities of IDH1-mutant gliomas may be a powerful therapeutic approach. This study aimed to investigate the roles of lysine demethylases, KDM6A and KDM6B, in the progression of IDH1-mutant gliomas. Using CRISPR/Cas9-mediated gene ablation, we generated IDH1-mutant glioma cell lines (MGG152 and TS603) with reduced KDM6A/6B expression. Our experiments incorporated molecular cloning, qRT-PCR, western blotting, apoptosis assays, oxidative stress assays, RNA sequencing, ATAC sequencing, and Cut&Run sequencing to examine the effects of KDM6A/6B loss. We observed reduced growth rates, morphological changes, increased H3K27me3 levels, and upregulation of TGF-β signaling and senescence-related genes upon KDM6A/6B loss. Further assays revealed no significant apoptosis but highlighted reactive oxygen species (ROS) elevation linked to TGF-β regulation. ß-galactosidase staining confirmed ROS-associated senescence. Additionally, mouse tumor formation studies using KDM6A/6B-depleted TS603 cells confirmed glioma-relevant histological features. Our findings reveal the critical functions of KDM6A and KDM6B in IDH1-mutant gliomas and provide insights into their potential as therapeutic targets for epigenetic interventions. These results open pathways for new strategies in glioma treatment through the modulation of epigenetic mechanisms. Citation Format: Sedef Sarac Yalcinkaya, Ebru Yilmaz, Alisan Kayabolen, Tugba Bagci-Onder. Targeting KDM6A and KDM6B histone demethylases to exploit epigenetic vulnerabilities in IDH mutant gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7190.