We sought to assess the biological function of m6A in TMZ resistance in GBM patients and investigate the underlying epigenetic mechanism by determining the critical targets of m6A. Our results indicated that TMZ treatment induced the expression of the m6A methyltransferase, METTL3, in GBM cells via the SOX4/EZH2/H3K27ac cascade, thereby promoting m6A modification of the transcripts of histone modification factors. This evidence concerns the gene EZH2 and glioblastoma.