RNA m ⁶A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail

Abstract

N6-Methyladenosine (m ⁶A) modification has been implicated in the progression of several cancers. We reveal that during epithelial-mesenchymal transition (EMT), one important step for cancer cell metastasis, m ⁶A modification of mRNAs increases in cancer cells. Deletion of methyltransferase-like 3 (METTL3) down-regulates m ⁶A, impairs the migration, invasion and EMT of cancer cells both in vitro and in vivo. m ⁶A-sequencing and functional studies confirm that Snail, a key transcription factor of EMT, is involved in m ⁶A-regulated EMT. m ⁶A in Snail CDS, but not 3’UTR, triggers polysome-mediated translation of Snail mRNA in cancer cells. Loss and gain functional studies confirm that YTHDF1 mediates m ⁶A-increased translation of Snail mRNA. Moreover, the upregulation of METTL3 and YTHDF1 act as adverse prognosis factors for overall survival (OS) rate of liver cancer patients. Our study highlights the critical roles of m ⁶A on regulation of EMT in cancer cells and translation of Snail during this process.

Abstract

RNA m6A methylation is known to be dysregulated in many cancers. Here, the authors show that m6A methylation of Snail mRNA regulates its translation with potential effects on epithelial mesenchymal transition.