miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions

Cell Cycle. 2011 Dec 15;10(24):4256-71. doi: 10.4161/cc.10.24.18552. Epub 2011 Dec 15.


Recently, the inhibition of epithelial-mesenchymal-transition (EMT) by p53 has been described as a new mode of tumor suppression which presumably prevents metastasis. Here we report that activation of p53 down-regulates the EMT-inducing transcription factor SNAIL via induction of the miR-34a/b/c genes. Suppression of miR-34a/b/c caused up-regulation of SNAIL and cells displayed EMT markers and related features, as enhanced migration and invasion. Ectopic miR-34a induced mesenchymal-epithelial-transition (MET) and down-regulation of SNAIL, which was mediated by a conserved miR-34a/b/c seed-matching sequence in the SNAIL 3'-UTR. miR-34a also down-regulated SLUG and ZEB1, as well as the stemness factors BMI1, CD44, CD133, OLFM4 and c-MYC. Conversely, the transcription factors SNAIL and ZEB1 bound to E-boxes in the miR-34a/b/c promoters, thereby repressing miR-34a and miR-34b/c expression. Since ectopic miR-34a prevented TGF-β-induced EMT, the repression of miR-34 genes by SNAIL and related factors is part of the EMT program. In conclusion, the frequent inactivation of p53 and/or miR-34a/b/c found in cancer may shift the equilibrium of these reciprocal regulations towards the mesenchymal state and thereby lock cells in a metastatic state.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Cloning, Molecular
  • Electrophoresis, Polyacrylamide Gel
  • Epithelial-Mesenchymal Transition / physiology*
  • Feedback, Physiological / physiology*
  • Fluorescent Antibody Technique
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Genetic Vectors / genetics
  • Humans
  • Luciferases
  • MicroRNAs / metabolism*
  • Microscopy, Confocal
  • Mitomycin
  • Real-Time Polymerase Chain Reaction
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*


  • 3' Untranslated Regions
  • MIRN34 microRNA, human
  • MicroRNAs
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Mitomycin
  • Luciferases