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Previous studies, including our study, have shown that aberrant N6\u2010methyladenosine (m<jats:sup>6<\/jats:sup>A) modification is implicated in GBM pathobiology. However, the roles and precise mechanisms of m<jats:sup>6<\/jats:sup>A modification in the regulation of TMZ resistance in GBM remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>m<jats:sup>6<\/jats:sup>A individual\u2010nucleotide\u2010resolution cross\u2010linking and immunoprecipitation sequencing (miCLIP\u2010seq) was performed to identify m<jats:sup>6<\/jats:sup>A modification of transcripts in TMZ\u2010resistant and \u2010sensitive tumors. To explore the role of METTL3 in TMZ resistance, TMZ\u2010resistant GBM cells were transfected with <jats:italic>METTL3<\/jats:italic> shRNA or overexpression lentivirus and then assessed by cell viability, tumor sphere formation, and apoptosis assays. An intracranial GBM xenograft model was developed to verify the effect of METTL3 depletion during TMZ treatment in vivo. ATAC\u2010seq, ChIP\u2010qPCR, and dual\u2010luciferase reporter assays were carried out to verify the role of SOX4\/EZH2 in the modulation of METTL3 expression upon TMZ treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated that TMZ treatment upregulated the expression of the m<jats:sup>6<\/jats:sup>A methyltransferase METTL3, thereby increasing m<jats:sup>6<\/jats:sup>A modification of histone modification\u2010related gene transcripts. METTL3 is required to maintain the features of GBM stem cells. When combined with TMZ, METTL3 silencing suppressed orthotopic TMZ\u2010resistant xenograft growth in a cooperative manner. Mechanistically, TMZ induced a SOX4\u2010mediated increase in chromatin accessibility at the <jats:italic>METTL3<\/jats:italic> locus by promoting H3K27ac levels and recruiting RNA polymerase II. Moreover, <jats:italic>METTL3<\/jats:italic> depletion affected the deposition of m<jats:sup>6<\/jats:sup>A on histone modification\u2010related gene transcripts, such as EZH2, leading to nonsense\u2010mediated mRNA decay. We revealed an important role of EZH2 in the regulation of <jats:italic>METTL3<\/jats:italic> expression, which was via an H3K27me3 modification\u2010independent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings uncover the fundamental mechanisms underlying the interplay of m<jats:sup>6<\/jats:sup>A RNA modification and histone modification in TMZ resistance and emphasize the therapeutic potential of targeting the SOX4\/EZH2\/METTL3 axis in the treatment of TMZ\u2010resistant GBM.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.553","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T07:28:57Z","timestamp":1631690937000},"source":"Crossref","is-referenced-by-count":70,"title":["Interplay of m<sup>6<\/sup>A and histone modifications contributes to temozolomide resistance in glioblastoma"],"prefix":"10.1002","volume":"11","author":[{"given":"Fuxi","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center Sun Yat\u2010sen University  Guangzhou China"},{"name":"Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences  Guangzhou China"},{"name":"Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat\u2010Sen University, Ministry of Education  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyun","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat\u2010Sen University, Ministry of Education  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaming","family":"Yu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Stem Cells and Tissue Engineering, Sun Yat\u2010Sen University, Ministry of Education  Guangzhou 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