The m6A methyltransferase METTL3 contributes to Transforming Growth Factor-beta-induced epithelial-mesenchymal transition of lung cancer cells through the regulation of JUNB
The m6A methyltransferase METTL3 contributes to Transforming Growth Factor-beta-induced epithelial-mesenchymal transition of lung cancer cells through the regulation of JUNB
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DOI：
10.1016/j.bbrc.2020.01.042
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发表时间：
2020-03-26
影响因子：
3.1
通讯作者：
Suzuki, Takeshi
中科院分区：
文献类型：
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作者：
Wanna-udom, Sasithorn;Terashima, Minoru;Suzuki, Takeshi
N6-甲基腺苷(M6A)是mRNAs最常见的内部化学修饰，参与包括多种癌症在内的多种病理过程。在本研究中，我们研究了m6A甲基转移酶METTL3在转化生长因子-β诱导的肺癌细胞系上皮-间充质转化(EMT)中的作用。在转化生长因子-β诱导的A549和LC2/ad肺癌细胞的EMT过程中，METTL3和m6A RNA修饰的表达增加。METTL3基因敲除可抑制转化生长因子-β诱导的细胞形态转化，增强细胞迁移能力，抑制CDH1/E-钙粘蛋白、FN1/纤维连接蛋白和Vim/Vimentin等EMT相关标志物基因的表达变化。机制研究表明，METTL3基因敲除降低了EMT的重要转录调控因子之一JunB的m6A修饰、总mRNA水平和mRNA稳定性。JunB的过表达部分挽救了METTL3基因敲除对EMT表型的抑制作用。本研究表明，m6A甲基转移酶METTL3在转化生长因子-β诱导的肺癌细胞EMT中是不可或缺的，它通过对JunB的调节而诱导肺癌细胞发生EMT。(C)2020 Elsevier Inc.保留所有权利。
N6-Methyladenosine (m6A) is the most common internal chemical modification of mRNAs involved in many pathological processes including various cancers. In this study, we investigated the role of m6A methyltransferase METTL3 in TGF-beta-induced epithelial-mesenchymal transition (EMT) of lung cancer cell lines. The expression of METTL3 and m6A RNA modification were increased during TGF-beta-induced EMT of A549 and LC2/ad lung cancer cells. Knockdown of METTL3 inhibited TGF-beta-induced morphological conversion of the cells, enhanced cell migration potential and the expression changes of EMT-related marker genes such as CDH1/E-cadherin, FN1/Fibronectin and VIM/Vimentin. Mechanistic investigations revealed that METTL3 knockdown decreased the m6A modification, total mRNA level and mRNA stability of JUNB, one of the important transcriptional regulators of EMT. Over-expression of JUNB partially rescued the inhibitory effects of METTL3 knockdown in the EMT phenotypes. This study demonstrates that m6A methyltransferase METTL3 is indispensable for TGF-beta-induced EMT of lung cancer cells through the regulation of JUNB. (C) 2020 Elsevier Inc. All rights reserved.