Snail represses the splicing regulator epithelial splicing regulatory protein 1 to promote epithelial-mesenchymal transition

J Biol Chem. 2012 Oct 19;287(43):36435-42. doi: 10.1074/jbc.M112.397125. Epub 2012 Sep 7.


Epithelial-mesenchymal transition (EMT), a tightly regulated process that is critical for development, is frequently re-activated during cancer metastasis and recurrence. We reported previously that CD44 isoform switching is critical for EMT and showed that the splicing factor ESRP1 inhibits CD44 isoform switching during EMT. However, the mechanism by which ESRP1 is regulated during EMT has not been fully understood. Here we show that the transcription repressor Snail binds to E-boxes in the ESRP1 promoter, causing repression of the ESRP1 gene. Biochemically, we define the mechanism by which ESRP1 regulates CD44 alternative splicing: ESRP1 binds to the intronic region flanking a CD44 variable exon and causes increased variable exon inclusion. We further show that ectopically expressing ESRP1 inhibits Snail-induced EMT, suggesting that down-regulation of ESRP1 is required for function by Snail in EMT. Together, these data reveal how the transcription factor Snail mediates EMT through regulation of a splicing factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing / physiology*
  • Animals
  • Cell Line, Tumor
  • Dogs
  • Epithelial-Mesenchymal Transition / physiology*
  • Exons / physiology
  • HEK293 Cells
  • Humans
  • Hyaluronan Receptors / biosynthesis*
  • Hyaluronan Receptors / genetics
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • RNA-Binding Proteins / biosynthesis*
  • RNA-Binding Proteins / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*


  • CD44 protein, human
  • ESRP1 protein, human
  • Hyaluronan Receptors
  • Protein Isoforms
  • RNA-Binding Proteins
  • Repressor Proteins