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

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Abstract
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/β‐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 β‐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/β‐catenin signaling.