Department of Otorhinolaryngology, The First Affiliated Hospital of University of South China, Hengyang, Hunan Province, China.
Department of Gastroenterology, The First Affiliated Hospital of University of South China, Hengyang, Hunan Province, China.
Kaohsiung J Med Sci. 2020 Nov;36(11):895-903. doi: 10.1002/kjm2.12266. Epub 2020 Jul 15.
The roles of RNA m6A modification in carcinogenesis have attracted much interest recently. However, the dysregulation of RNA m6A regulators (writers, readers, and erasers) in nasopharyngeal carcinoma (NPC) has never been reported. In this study, we showed that METTL3, one of the writers, was upregulated in NPC. Functional studies revealed that METTL3 promoted the migration and invasion of NPC cells. However, METTL3 knockdown reversed this effect and inhibited the migration, invasion and metastasis of NPC cells. METTL3 activated the luciferase activity of TOPflash (a reporter for beta-catenin/TCF signaling), and downregulation of METTL3 inhibited the expression of beta-catenin/TCF target genes vimentin and N-cadherin, which are two regulators of epithelial-mesenchymal transition. Moreover, dominant negative beta-catenin blocked the migration and invasion of NPC cells. Further mechanistic studies showed that METTL3 silencing decreased the m6A methylation and total mRNA levels of Tankyrase, a negative regulator of axin. Moreover, Tankyrase overexpression abrogated the repressive effects of METTL3 silencing on the migration of NPC cells. Collectively, our study demonstrates the oncogenic roles of METTL3 in NPC, and suggests that METTL3 might be a therapeutic target for NPC.
RNA m6A 修饰在致癌作用中的作用最近引起了广泛关注。然而，鼻咽癌（NPC）中 RNA m6A 调节因子（写入器、读取器和橡皮擦）的失调从未被报道过。在这项研究中，我们表明，METTL3 是写入器之一，在 NPC 中上调。功能研究表明，METTL3 促进 NPC 细胞的迁移和侵袭。然而，METTL3 的敲低逆转了这种效应，抑制了 NPC 细胞的迁移、侵袭和转移。METTL3 激活了 TOPflash（β-连环蛋白/TCF 信号的报告基因）的荧光素酶活性，而下调 METTL3 抑制了上皮-间充质转化的两个调节因子波形蛋白和 N-钙粘蛋白的 β-连环蛋白/TCF 靶基因的表达。此外，显性负β-连环蛋白阻断 NPC 细胞的迁移和侵袭。进一步的机制研究表明，METTL3 沉默降低了 Tankyrase 的 m6A 甲基化和总 mRNA 水平，Tankyrase 是轴突的负调节剂。此外，Tankyrase 的过表达消除了 METTL3 沉默对 NPC 细胞迁移的抑制作用。总之，我们的研究表明 METTL3 在 NPC 中的致癌作用，并表明 METTL3 可能是 NPC 的治疗靶点。
