m6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis (Retracted Article)
m6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis (Retracted Article)
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DOI：
10.1186/s13045-019-0830-6
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发表时间：
2019-12-09
影响因子：
28.5
通讯作者：
Su, Guoming
中科院分区：
文献类型：
--
作者：
Jin, Dan;Guo, Jiwei;Su, Guoming
背景：胃L3是一种RNA甲基转移酶，介导m（6）A修饰，并参与mRNA的生物合成、降解和翻译。然而，CD 3L 3通过调节MALAT 1-miR-1914- 3 p-YAP轴活性诱导非小细胞肺癌耐药和转移的生物机制尚不清楚。方法：采用qPCR分析mRNA的表达。通过蛋白质印迹和免疫荧光染色分析蛋白质水平。CCK-8法检测细胞增殖。分别通过伤口愈合和transwell实验分析细胞迁移和侵袭。启动子活性和基因转录通过荧光素酶报告基因分析。结果：L3使雅普的m（6）A修饰增加。YTHDF 3、YTHDF 1和eIF 3b通过与翻译起始机制的相互作用直接促进雅普翻译。此外，由于胃L3介导的较高水平的m（6）A修饰，MALAT 1的RNA水平增加。同时，胃L3/YTHDF 3复合物提高了MALAT 1的稳定性。此外，MALAT 1作为竞争性内源性RNA发挥作用，其通过雅普吸收miR-1914- 3 p以促进NSCLC的侵袭和转移。结论：由胃L3启动的m（6）A mRNA甲基化通过募集YTHDF 1/3和eIF 3b进入翻译起始复合物促进YAP mRNA的翻译，并通过调节MALAT 1-miR-1914- 3 p-YAP轴增加雅普mRNA的稳定性。雅普的表达和活性增加可诱导NSCLC的耐药和转移。
Background: METTL3 is an RNA methyltransferase that mediates m(6)A modification and is implicated in mRNA biogenesis, decay, and translation. However, the biomechanism through which METTL3 regulates MALAT1-miR-1914-3p-YAP axis activity to induce NSCLC drug resistance and metastasis is not very clear.Methods: The expression of mRNA was analyzed by qPCR assays. Protein levels were analyzed by western blotting and immunofluorescent staining. Cellular proliferation was detected by CCK8 assays. Cell migration and invasion were analyzed by wound healing and transwell assays, respectively. Promoter activities and gene transcription were analyzed by luciferase reporter assays. Finally, m(6)A modification was analyzed by MeRIP.Results: METTL3 increased the m(6)A modification of YAP. METTL3, YTHDF3, YTHDF1, and eIF3b directly promoted YAP translation through an interaction with the translation initiation machinery. Moreover, the RNA level of MALAT1 was increased due to a higher level of m(6)A modification mediated by METTL3. Meanwhile, the stability of MALAT1 was increased by METTL3/YTHDF3 complex. Additionally, MALAT1 functions as a competing endogenous RNA that sponges miR-1914-3p to promote the invasion and metastasis of NSCLC via YAP. Furthermore, the reduction of YAP m(6)A modification by METTL3 knockdown inhibits tumor growth and enhances sensitivity to DDP in vivo.Conclusion: Results indicated that the m(6)A mRNA methylation initiated by METTL3 promotes YAP mRNA translation via recruiting YTHDF1/3 and eIF3b to the translation initiation complex and increases YAP mRNA stability through regulating the MALAT1-miR-1914-3p-YAP axis. The increased YAP expression and activity induce NSCLC drug resistance and metastasis.