RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail

Nat Commun. 2019 May 6;10(1):2065. doi: 10.1038/s41467-019-09865-9.

Abstract

N6-Methyladenosine (m6A) 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, m6A modification of mRNAs increases in cancer cells. Deletion of methyltransferase-like 3 (METTL3) down-regulates m6A, impairs the migration, invasion and EMT of cancer cells both in vitro and in vivo. m6A-sequencing and functional studies confirm that Snail, a key transcription factor of EMT, is involved in m6A-regulated EMT. m6A 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 m6A-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 m6A on regulation of EMT in cancer cells and translation of Snail during this process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Cell Line, Tumor
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Kaplan-Meier Estimate
  • Liver / pathology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • RNA / metabolism*
  • RNA Processing, Post-Transcriptional
  • RNA-Binding Proteins / metabolism
  • Snail Family Transcription Factors / genetics*
  • Tissue Array Analysis
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • RNA-Binding Proteins
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • YTHDF1 protein, human
  • RNA
  • N-methyladenosine
  • Methyltransferases
  • METTL3 protein, human
  • Adenosine