Abstract
N6-methyladenosine (m6A) 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 m6A methylation plays essential roles in tumor development. However, the relationship between m6A 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 (Mettl3Mut/−) cells. The expression of TGFβ1 was up-regulated, while self-stimulated expression of TGFβ1 was suppressed in Mettl3Mut/− cells. We further revealed that m6A promoted TGFB1 mRNA decay, but impaired TGFB1 translation progress. Besides this, the autocrine of TGFβ1 was disrupted in Mettl3Mut/− cells via interrupting TGFβ1 dimer formation. Lastly, we found that Snail, which was down-regulated in Mettl3Mut/− cells, was a key factor responding to TGFβ1-induced EMT. Together, our research demonstrated that m6A performed multi-functional roles in TGFβ1 expression and EMT modulation, suggesting the critical roles of m6A in cancer progression regulation.
Highlights
In eukaryotes, gene expression is regulated by transcriptional and post-transcriptional processes.Among the over 100 modifications in mRNA, N6-methyladenosine (m6 A) is one of the most abundant internal modifications [1,2,3]
To further investigate the effect of methyltransferase-like 3 (METTL3) on epithelial–mesenchymal transition (EMT), we treated cells with 10 ng/mL TGFβ1, which has been considered to be the major EMT inducer in cancer cells. Both wound healing assay and Transwell assay showed that cell migration and invasion of control HeLa cells were successfully enhanced by TGFβ1, while there was no significant difference in Mettl3Mut/− cells (Figure 1a,b)
We showed that TGFβ1 failed to induce EMT in Mettl3Mut/− cells, and the
Summary
Among the over 100 modifications in mRNA, N6-methyladenosine (m6 A) is one of the most abundant internal modifications [1,2,3]. This methylation process is catalyzed by “writer” methyltransferases, including methyltransferase-like 3 and 14 (METTL3 and METTL14) and other cofactors, such as Wilm’. A growing body of work provides evidence showing that m6 A mRNA modification acts as a regulator of the mRNA life cycle, including pre-mRNA splicing [6,7,8], nucleo-cytoplasmic export [5,9,10], mRNA decay [11,12], and mRNA translation [13,14]. The METTL3–METTL14 heterodimeric complex generates m6 A on mRNA, where METTL3 contributes the catalytic residues and METTL14 provides
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