The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene

Abstract

N6-methyladenosine (m6A) modification can alter gene expression by regulating RNA splicing, stability, translocation, and translation. Emerging evidence shows that m6A modification plays an important role in cancer development and progression, including cell proliferation, migration and invasion, cell apoptosis, autophagy, and drug resistance. Until now, the role of m6A modification mediated autophagy in cancer drug resistance is still unclear. In this study, we found that m6A methyltransferase METTL3-mediated autophagy played an important role in reversing gefitinib resistance by β-elemene in non-small cell lung cancer (NSCLC) cells. Mechanistically, in vitro and in vivo studies indicated that β-elemene could reverse gefitinib resistance in NSCLC cells by inhibiting cell autophagy process in a manner of chloroquine. β-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and LC3B-II. Moreover, both β-elemene and gefitinib decreased the level of m6A methylation of gefitinib resistance cells. METTL3 was higher expressed in lung adenocarcinoma tissues than that of paired normal tissues, and was involved in the gefitinib resistance of NSCLC cells. Furthermore, METTL3 positively regulated autophagy by increasing the critical genes of autophagy pathway such as ATG5 and ATG7. In conclusion, our study unveiled the mechanism of METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by β-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

“…In particular, elimination of miR-143-3p and vasohibin-1 (VASH1) induced by METTL3 resulted in enhanced brain metastasis [ 81 ]. Moreover, METTL3 could positively mediate the autophagy related pathway and further induce gefitinib resistance, indicating the potential role of METTL3 in the treatment of NSCLC [ 82 ].…”

“…From another perspective, METTL3 was commonly related to drug resistance in tumors. Chemoresistance induced by METTL3 were detected in several kinds of cancers [ 41 , 66 , 82 , 105 ], indicating that functional inhibition of METTL3 might restore the chemosensitivity of tumor cells [ 127 ]. In addition, depletion of METTL3/14 could strengthen the therapeutic effect of anti-PD-1 therapy through activating the IFN pathway [ 68 ].…”

Role of RNA N6-Methyladenosine Modification in Male Infertility and Genital System Tumors

“…Downregulation of m6A demethylase FTO and ALKBH5 increased the modification of the FZD10mRNA gene to reduce the sensitivity of ovarian epithelial cell carcinoma to PARPI by upregulating the Wnt/β-catenin pathway ( Fukumoto et al, 2019 ). m6A methyltransferase METTL3 mediated autophagy increases the sensitivity of non-small cell lung cancer cells to gefitinib by β-elemene ( Liu S. et al, 2020 ). And METTL3 also directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce drug resistance and metastasis of non-small cell lung cancer ( Jin et al, 2019 ).…”

Importance of N6‑methyladenosine RNA modification in lung cancer (Review)

“…Mechanistically, β-elemene can reverse gefitinib resistance by inhibiting the late stage of autophagy in a manner of chloroquine, which inhibits the maturation of autophagosomes into autolysosomes through attenuating the lysosomal acidification. In this reversing process, METTL3 can positively regulate this autophagy process by targeting autophagy protein (ATG5), ATG7, light chain 3B (LC3B) and Sequestosome 1 (SQSTM1) ( 83 ). Functional enrichment analysis of the m 6 A-modified genes revealed that m 6 A methylation might modify the cell cycle to influence the response to afatinib.…”