Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Ishikawa, Japan.
Division of Education for Global Standard, Institute of Liberal Arts and Science, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Ishikawa, Japan.
Biochem Biophys Res Commun. 2020 Mar 26;524(1):150-155. doi: 10.1016/j.bbrc.2020.01.042. Epub 2020 Jan 22.
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-β-induced epithelial-mesenchymal transition (EMT) of lung cancer cell lines. The expression of METTL3 and m6A RNA modification were increased during TGF-β-induced EMT of A549 and LC2/ad lung cancer cells. Knockdown of METTL3 inhibited TGF-β-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-β-induced EMT of lung cancer cells through the regulation of JUNB.
N6-甲基腺苷（m6A）是参与许多病理过程的 mRNAs 中最常见的内部化学修饰，包括各种癌症。在这项研究中，我们研究了 m6A 甲基转移酶 METTL3 在 TGF-β诱导的肺癌细胞系上皮-间充质转化（EMT）中的作用。在 TGF-β诱导的 A549 和 LC2/ad 肺癌细胞 EMT 过程中，METTL3 的表达和 m6A RNA 修饰增加。METTL3 的敲低抑制了细胞的 TGF-β诱导的形态转化，增强了细胞迁移潜力和 EMT 相关标记基因如 CDH1/E-钙黏蛋白、FN1/纤连蛋白和 VIM/Vimentin 的表达变化。机制研究表明，METTL3 的敲低降低了 JUNB 的 m6A 修饰、总 mRNA 水平和 mRNA 稳定性，JUNB 是 EMT 的重要转录调节因子之一。JUNB 的过表达部分挽救了 METTL3 敲低在 EMT 表型中的抑制作用。这项研究表明，m6A 甲基转移酶 METTL3 通过调节 JUNB 对 TGF-β诱导的肺癌细胞 EMT 是不可或缺的。
