KDM6B promotes VEGFA expression and vasculogenic mimicry in glioblastoma cells under hypoxia conditions.

Malignant gliomas, particularly glioblastoma (GBM), exhibit hallmark features of aberrant angiogenesis and elevated vascular endothelial growth factor A (VEGFA) expression. While VEGFA overexpression is a key driver of GBM progression, the underlying molecular mechanisms remain incompletely elucidated. Accumulating evidence highlights the critical role of epigenetic modifications in regulating tumor angiogenesis. Herein, this study investigated the regulatory function of the histone demethylase KDM6B in VEGFA expression and GBM angiogenesis. Retrospective clinical analysis confirmed that VEGFA-targeted adjuvant therapy moderately prolongs progression-free survival (PFS) in GBM patients. Bioinformatics analysis of GBM specimens revealed a significant positive correlation between VEGFA and KDM6B expression levels. In vitro experiments demonstrated that both mRNA and protein levels of VEGFA were markedly upregulated in GBM cells under hypoxic conditions. Pharmacological inhibition of KDM6B using its specific inhibitor GSK-J4 effectively attenuated hypoxia-induced VEGFA overexpression. Furthermore, KDM6B was shown to promote vasculogenic mimicry (VM) formation in GBM cells under hypoxia. Collectively, these findings uncover a novel epigenetic mechanism by which KDM6B regulates VEGFA expression and VM formation in GBM. The study provides a compelling rationale for targeting KDM6B to enhance the efficacy of anti-angiogenic therapies in GBM treatment.