Tumour Suppressor HIC1 - a novel inhibitor of Wnt Signalling

Abstract

1. ABSTRACT In all metazoan organisms Wnt ligands regulate various developmental and physiological processes during embryogenesis and also in adult tissues. Moreover, deregulation in Wnt-related signalling is associated with several human disorders including cancer. In the so-called canonical pathway, activation of the Wnt receptor complex Frizzled/LRP triggers a complex network of molecular events that ultimately lead to the stabilization of β-catenin and formation of TCF/β- catenin heterodimers in the nucleus. These protein complexes drive expression of a specific set of genes that control the cell fate decision. The Wnt pathway is tightly regulated by several mostly negative feedback loops involving scores of extracellular, cytoplasmic or nuclear proteins. Recently, we have identified tumour suppressor Hypermethylated in cancer 1 (HIC1) as a negative modulator of canonical Wnt signalling. The HIC1 gene encodes a BTB/POZ-zinc finger transcriptional repressor. Interestingly, the HIC1-dependent repression of the TCF/β-catenin- dependent genes is not mediated by direct association of HIC1 with the regulatory regions of the Wnt-responsive genes but rather by a sequestration of TCF/β-catenin complexes to the nuclear speckle-like structures - the HIC bodies. These data indicate quite a pleiotropic role of HIC1...