Journal Article

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

Chen, Shuyang, Yu, Peng, Zhang, Boxiang, Yan, Yuting, Li, Guangyu, Sun, Yongqing

2026

Overview

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. 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. 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. 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.