HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies

EMBO J. 2006 Jun 7;25(11):2326-37. doi: 10.1038/sj.emboj.7601147. Epub 2006 May 25.


The hypermethylated in cancer 1 (HIC1) gene is epigenetically inactivated in cancer, and in addition, the haploinsufficiency of HIC1 is linked to the development of human Miller-Dieker syndrome. HIC1 encodes a zinc-finger transcription factor that acts as a transcriptional repressor. Additionally, the HIC1 protein oligomerizes via the N-terminal BTB/POZ domain and forms discrete nuclear structures known as HIC1 bodies. Here, we provide evidence that HIC1 antagonizes the TCF/beta-catenin-mediated transcription in Wnt-stimulated cells. This appears to be due to the ability of HIC1 to associate with TCF-4 and to recruit TCF-4 and beta-catenin to the HIC1 bodies. As a result of the recruitment, both proteins are prevented from association with the TCF-binding elements of the Wnt-responsive genes. These data indicate that the intracellular amounts of HIC1 protein can modulate the level of the transcriptional stimulation of the genes regulated by canonical Wnt/beta-catenin signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein
  • Cell Nucleus / metabolism*
  • Culture Media, Conditioned
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Humans
  • Kruppel-Like Transcription Factors
  • Mice
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • Signal Transduction / physiology*
  • TCF Transcription Factors / genetics
  • TCF Transcription Factors / metabolism*
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • AXIN2 protein, human
  • Axin Protein
  • Culture Media, Conditioned
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • HIC1 protein, human
  • Kruppel-Like Transcription Factors
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Tcf7l2 protein, mouse
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin