Histone acetyltransferase Kat2a regulates glioma stem cell differentiation via Hsp90aa1-dependent oxidative...

Glioblastoma (GBM) is mainly dependent on glioma stem cells (GSCs) and aberrant epigenetic modifications for its malignancy. Lysine acetyltransferase 2A (KAT2A) is involved in histone acetylation and has been implicated in stem cell differentiation and metabolic plasticity; however, its precise role in GSC differentiation remains elusive. In this study, we investigated the mechanisms of Kat2a regulates GSC differentiation and metabolic reprogramming. We found that KAT2A is highly expressed in GBM and GSCs. Downregulation of Kat2a reduced the proliferation and self-renewal ability of GSCs while promoting their differentiation toward a neuronal lineage. Transcriptomic and metabolomic analyses were performed to identify potential downstream targets, and chromatin immunoprecipitation (ChIP) was used to validate the underlying molecular mechanisms. Metabolic function was assessed by measuring mitochondrial membrane potential (MMP), intracellular reactive oxygen species (ROS), mitochondrial ROS, and ATP production. Oxidative phosphorylation (OXPHOS) status was evaluated based on oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Our results showed that Kat2a triggers H3K9 acetylation at the Hsp90aa1 promoter. Mutation Loop3 residues within acetyl-CoA binding domain of Kat2a reduced H3K9 acetylation and Hsp90aa1 expression, which are required for mitochondrial OXPHOS and the maintenance of GSC stemness. In orthotopic glioma mouse models, downregulation of Kat2a significantly suppressed tumor growth in vivo. Together, these findings demonstrate that Kat2a promotes Hsp90aa1 expression via the H3K9 acetylation, thereby maintaining GSC stemness through metabolic reprogramming.