Requirement of cell cycle and apoptosis regulator 1 for target gene activation by Wnt and β-catenin and for anchorage-independent growth of human colon carcinoma cells

Abstract

Aberrant Wnt signaling promotes oncogenesis by increasing cellular levels of β-catenin, which associates with DNA-bound transcription factors and activates Wnt target genes. However, the molecular mechanism by which β-catenin mediates gene expression is still poorly understood. Here, we show that cell cycle and apoptosis regulator 1 (CCAR1), which was recently shown to function as a transcriptional coactivator for nuclear receptors, also interacts with β-catenin and enhances the ability of β-catenin to activate expression of transiently transfected reporter genes. Furthermore, association of CCAR1 with the promoter of an endogenons Wnt/β-catenin target gene in a colon cancer cell line depends on the presence of β-catenin. Depletion of CCAR1 inhibits expression of several Wnt/β-catenin target genes and suppresses anchorage-independent growth of the colon cancer cell line. Thus, CCAR1 is a novel component of Wnt/)β- catenin signaling that plays an important role in transcriptional regulation by β-catenin and that, therefore, may represent a novel target for therapeutic intervention in cancers involving aberrantly activated Wnt/β-catenin signaling. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.