Hypoxia-induced PRMT6 expression promotes temozolomide chemoresistance in glioblastoma via G3BP1.

BACKGROUND: Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, is associated with extremely poor patient prognosis. Temozolomide (TMZ) resistance remains a major cause of treatment failure. Protein arginine methyltransferase 6 (PRMT6) plays critical roles in tumorigenesis, but its function and regulatory mechanisms in GBM TMZ resistance have not been elucidated. While the hypoxic microenvironment is a hallmark feature of GBM, its epigenetic regulatory mechanisms in drug resistance remain unclear.

METHODS: We analyzed PRMT6 expression and prognostic value in GBM using public databases (TCGA, CGGA). TMZ resistance was assessed through in vitro assays (CCK-8, flow cytometry, colony formation) and in vivo xenograft models. Molecular mechanisms of the HIF-1α/PRMT6/G3BP1 axis were investigated via RNA sequencing, ChIP-qPCR, dual-luciferase reporter assays, and co-immunoprecipitation.

RESULTS: PRMT6 was highly expressed in GBM and correlated with poor prognosis. Hypoxia transcriptionally activated PRMT6 through HIF-1α. Elevated PRMT6 expression promoted TMZ resistance, while its knockdown enhanced drug sensitivity. Mechanistically, PRMT6 interacted with transcription factor GABPA to upregulate stress granule core protein G3BP1, subsequently suppressing pro-apoptotic BCL2L13 and conferring chemoresistance. In vivo studies confirmed that both PRMT6 and G3BP1 significantly influenced TMZ resistance.

CONCLUSION: This study provides evidence that hypoxia mediates TMZ resistance in GBM through the HIF-1α/PRMT6/G3BP1 axis, identifying PRMT6 and G3BP1 as promising therapeutic targets to overcome chemoresistance.