The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network

Oncogene. 2019 May;38(19):3667-3680. doi: 10.1038/s41388-019-0683-z. Epub 2019 Jan 18.


N6-methyladenosine (m6A) is the most abundant modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in many bioprocesses. However, its functions in bladder cancer (BCa) remain elusive. Here, we discovered that methyltransferase-like 3 (METTL3), a major RNA N6-adenosine methyltransferase, was significantly up-regulated in human BCa. Knockdown of METTL3 drastically reduced BCa cell proliferation, invasion, and survival in vitro and tumorigenicity in vivo. On the other hand, overexpression of METTL3 significantly promoted BCa cell growth and invasion. Through transcriptome sequencing, m6A sequencing and m6A methylated RNA immuno-precipitation quantitative reverse-transcription polymerase chain reaction, we revealed the profile of METTL3-mediated m6A modification in BCa cells for the first time. AF4/FMR2 family member 4 (AFF4), two key regulators of NF-κB pathway (IKBKB and RELA) and MYC were further identified as direct targets of METTL3-mediated m6A modification. In addition, we showed that besides NF-κB, AFF4 binds to the promoter of MYC and promotes its expression, implying a novel multilevel regulatory network downstream of METTL3. Our results uncovered an AFF4/NF-κB/MYC signaling network operated by METTL3-mediated m6A modification and provided insight into the mechanisms of BCa progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / genetics
  • Adenosine / metabolism
  • Animals
  • Cell Movement
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Male
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Mice, Inbred BALB C
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcriptional Elongation Factors / metabolism*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology*
  • Xenograft Model Antitumor Assays


  • AFF4 protein, human
  • Proto-Oncogene Proteins c-myc
  • RELA protein, human
  • Repressor Proteins
  • Transcription Factor RelA
  • Transcriptional Elongation Factors
  • N-methyladenosine
  • Methyltransferases
  • METTL3 protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • Adenosine