N6-Methyladenosine Regulates the Expression and Secretion of TGFβ1 to Affect the Epithelial-Mesenchymal Transition of Cancer Cells

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 (Mettl3^Mut/-) cells. The expression of TGFβ1 was up-regulated, while self-stimulated expression of TGFβ1 was suppressed in Mettl3^Mut/- cells. We further revealed that m⁶A promoted TGFB1 mRNA decay, but impaired TGFB1 translation progress. Besides this, the autocrine of TGFβ1 was disrupted in Mettl3^Mut/- cells via interrupting TGFβ1 dimer formation. Lastly, we found that Snail, which was down-regulated in Mettl3^Mut/- 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.

Keywords: EMT; TGFβ1; m6A.