Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Cells. 2020 Jan 25;9(2):296. doi: 10.3390/cells9020296.
N6-methyladenosine (mA) is the most abundant modification on eukaryotic mRNA, which regulates all steps of the mRNA life cycle. An increasing number of studies have shown that mA methylation plays essential roles in tumor development. However, the relationship between mA and the progression of cancers remains to be explored. Here, we reported that transforming growth factor-β (TGFβ1)-induced epithelial-mesenchymal transition (EMT) was inhibited in methyltransferase-like 3 (METTL3) knockdown (Mettl3) cells. The expression of TGFβ1 was up-regulated, while self-stimulated expression of TGFβ1 was suppressed in Mettl3 cells. We further revealed that mA promoted TGFB1 mRNA decay, but impaired TGFB1 translation progress. Besides this, the autocrine of TGFβ1 was disrupted in Mettl3 cells via interrupting TGFβ1 dimer formation. Lastly, we found that Snail, which was down-regulated in Mettl3 cells, was a key factor responding to TGFβ1-induced EMT. Together, our research demonstrated that mA performed multi-functional roles in TGFβ1 expression and EMT modulation, suggesting the critical roles of mA in cancer progression regulation.
N6-甲基腺苷（m6A）是真核 mRNA 上最丰富的修饰，调节 mRNA 生命周期的所有步骤。越来越多的研究表明，m6A 甲基化在肿瘤发展中起着至关重要的作用。然而，m6A 与癌症进展之间的关系仍有待探索。在这里，我们报道转化生长因子-β（TGFβ1）诱导的上皮-间充质转化（EMT）在甲基转移酶样 3（METTL3）敲低（Mettl3）细胞中受到抑制。TGFβ1 的表达上调，而 Mettl3 细胞中 TGFβ1 的自我刺激表达受到抑制。我们进一步揭示 m6A 促进 TGFB1 mRNA 降解，但阻碍 TGFB1 翻译进展。除此之外，TGFβ1 自分泌在 Mettl3 细胞中被破坏，通过中断 TGFβ1 二聚体形成。最后，我们发现 Mettl3 细胞中下调的 Snail 是响应 TGFβ1 诱导的 EMT 的关键因素。总之，我们的研究表明 m6A 在 TGFβ1 表达和 EMT 调节中发挥了多功能作用，表明 m6A 在癌症进展调控中的关键作用。
