RORα Attenuates Wnt/β-Catenin Signaling by PKCα-Dependent Phosphorylation in Colon Cancer

Summary: Wnt family members play diverse roles in development and disease. Noncanonical Wnt ligands can inhibit canonical Wnt signaling depending on the cellular context; however, the underlying mechanism of this antagonism remains poorly understood. Here we identify a specific mechanism of orphan nuclear receptor RORα-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKCα-dependent phosphorylation on serine residue 35 of RORα is crucial to link RORα to Wnt/β-catenin signaling, which exerts inhibitory function of the expression of Wnt/β-catenin target genes. Intriguingly, there is a significant correlation of reduction of RORα phosphorylation in colorectal tumor cases compared to their normal counterpart, providing the clinical relevance of the findings. Our data provide evidence for a role of RORα, functioning at the crossroads between the canonical and the noncanonical Wnt signaling pathways, in mediating transrepression of the Wnt/β-catenin target genes, thereby providing new approaches for the development of therapeutic agents for human cancers. [Copyright &y& Elsevier]