Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching

Pigment Cell Melanoma Res. 2011 Aug;24(4):631-42. doi: 10.1111/j.1755-148X.2011.00871.x. Epub 2011 Jun 9.


Recent observations suggest that melanoma cells drive disease progression by switching back and forth between phenotypic states of proliferation and invasion. Phenotype switching has been linked to changes in Wnt signalling, and we therefore looked for cell phenotype-specific differences in the levels and activity of β-catenin and its LEF/TCF co-factors. We found that while cytosolic β-catenin distribution is phenotype-specific (membrane-associated in proliferative cells and cytosolic in invasive cells), its nuclear distribution and activity is not. Instead, the expression patterns of two β-catenin co-factors, LEF1 and TCF4, are both phenotype-specific and inversely correlated. LEF1 is preferentially expressed by differentiated/proliferative phenotype cells and TCF4 by dedifferentiated/invasive phenotype cells. Knock-down experiments confirmed that these co-factors are important for the phenotype-specific expression of M-MITF, WNT5A and other genes and that LEF1 suppresses TCF4 expression independently of β-catenin. Our data show that melanoma cell phenotype switching behaviour is regulated by differential LEF1/TCF4 activity.

Publication types

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

MeSH terms

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Silencing / drug effects
  • Humans
  • Lymphoid Enhancer-Binding Factor 1 / genetics*
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Models, Biological
  • Neoplasm Invasiveness
  • Phenotype
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology*
  • Transcription Factor 4
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Wnt Proteins / pharmacology
  • beta Catenin / metabolism


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin