m6A RNA methylation regulates the transcription factors JUN and JUNB in TGF-β-induced epithelial-mesenchymal transition of lung cancer cells

J Biol Chem. 2022 Nov;298(11):102554. doi: 10.1016/j.jbc.2022.102554. Epub 2022 Sep 29.


N6-methyladenosine (m6A) is the most common internal chemical modification of mRNAs involved in many pathological processes including various cancers. In this study, we investigated the m6A-dependent regulation of JUN and JUNB transcription factors (TFs) during transforming growth factor-beta-induced epithelial-mesenchymal transition (EMT) of A549 and LC2/ad lung cancer cell lines, as the function and regulation of these TFs within this process remains to be clarified. We found that JUN and JUNB played an important and nonredundant role in the EMT-inducing gene expression program by regulating different mesenchymal genes and that their expressions were controlled by methyltransferase-like 3 (METTL3) m6A methyltransferase. METTL3-mediated regulation of JUN expression is associated with the translation process of JUN protein but not with the stability of JUN protein or mRNA, which is in contrast with the result of m6A-mediated regulation of JUNB mRNA stability. We identified the specific m6A motifs responsible for the regulation of JUN and JUNB in EMT within 3'UTR of JUN and JUNB. Furthermore, we discovered that different m6A reader proteins interacted with JUN and JUNB mRNA and controlled m6A-dependent expression of JUN protein and JUNB mRNA. These results demonstrate that the different modes of m6A-mediated regulation of JUN and JUNB TFs provide critical input in the gene regulatory network during transforming growth factor-beta-induced EMT of lung cancer cells.

Keywords: RNA methylation; cancer biology; epithelial–mesenchymal transition; gene expression; m6A reader protein; mRNA stability; translation regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epithelial-Mesenchymal Transition* / genetics
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • RNA, Messenger / genetics
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factors / metabolism


  • Transforming Growth Factor beta
  • RNA, Messenger
  • Transcription Factor AP-1
  • Methyltransferases
  • Transforming Growth Factors
  • METTL3 protein, human
  • JunB protein, human
  • Transcription Factors