AUTHOR=Shi Jia , Chen Gang , Dong Xuchen , Li Haoran , Li Suwen , Cheng Shan , Li Yongdong , Wang Liping , Yuan Jiaqi , Qian Zhiyuan , Dong Jun 

TITLE=METTL3 Promotes the Resistance of Glioma to Temozolomide via Increasing MGMT and ANPG in a m6A Dependent Manner

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.702983

DOI=10.3389/fonc.2021.702983

ISSN=2234-943X

ABSTRACT=<p>Acquired chemoresistance is a major limiting factor in the clinical treatment of glioblastoma (GBM). However, the mechanism by which GBM acquires therapeutic resistance remains unclear. Here, we aimed to investigate whether METTL3-mediated N6-methyladenosine (m<sup>6</sup>A) modification contributes to the temozolomide (TMZ) resistance in GBM. We demonstrated that METTL3 METTL3-mediated m<sup>6</sup>A modification were significantly elevated in TMZ-resistant GBM cells. Functionally, METTL3 overexpression impaired the TMZ-sensitivity of GBM cells. In contrast, METTL3 silencing or DAA-mediated total methylation inhibition improved the sensitivity of TMZ-resistant GBM cells to TMZ <italic>in vitro</italic> and <italic>in vivo</italic>. Furthermore, we found that two critical DNA repair genes (MGMT and APNG) were m<sup>6</sup>A-modified by METTL3, whereas inhibited by METTL3 silencing or DAA-mediated total methylation inhibition, which is crucial for METTL3-improved TMZ resistance in GBM cells. Collectively, METTL3 acts as a critical promoter of TMZ resistance in glioma and extends the current understanding of m<sup>6</sup>A related signaling, thereby providing new insights into the field of glioma treatment.</p>