Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway

Abstract β-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free β-catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3β (GSK3β) or p53-inducible Siah-1. Dysregulation of β-catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of β-catenin. In this proteasomal pathway, RXR agonists induce degradation of β-catenin and RXRα and repress β-catenin-mediated transcription. In vivo, β-catenin interacts with RXRα in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3β inhibitors or deletion of the GSK3β-targeted sequence from β-catenin. In APC- and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous β-catenin via RXRα. Interestingly, deletion of the RXRα A/B region abolished ligand-induced β-catenin degradation but not RXRα-mediated transactivation. RXRα-mediated inactivation of oncogenic β-catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of β-catenin turnover and related biological events.