Targeting the KAT7/H3K14ac/RAC2 Axis Mediates OXPHOS to Promote Stemness Maintenance and Malignancy in Glioblastoma [ChIP-Seq]

Here, we elucidate a novel epigenetic-metabolic axis mediated by the histone acetyltransferase KAT7 that orchestrates oxidative phosphorylation (OXPHOS) dominance in GSCs. Through a multiomics analysis, we demonstrated that KAT7 is preferentially upregulated in GBM, particularly in the classical subtype and in GSC-enriched populations, where it activates RAC2 expression via H3K14 acetylation of its promoter.

Mechanistically, KAT7-mediated RAC2 upregulation triggers PAK1/2/3 phosphorylation, increasing tricarboxylic acid cycle (TCA) and ATP production. Genetic ablation of KAT7 impairs GSC self-renewal, induces apoptosis, and suppresses tumor growth in orthotopic xenograft models. Conversely, KAT7 overexpression or pharmacological activation of the KAT7–RAC2 axis restores metabolic fitness and malignant phenotypes.