RORα Attenuates Wnt/β-Catenin Signaling by PKCα-Dependent Phosphorylation in Colon Cancer
Authors
Ji Min Lee ; Ik Soo Kim ; Hyunkyung Kim ; Jason S. Lee ; Kyeongkyu Kim ; Hwa Young Yim ; Jiyeong Jeong ; Jung Hwa Kim ; Ji-Young Kim ; Hanna Lee ; Sang-Beom Seo ; Hogeun Kim ; Michael G. Rosenfeld ; Keun Il Kim ; Sung Hee Baek
Carcinoma/metabolism* ; Cell Line ; Colonic Neoplasms/metabolism* ; Gene Expression Regulation ; Humans ; Nuclear Receptor Subfamily 1, Group F, Member 1/chemistry ; Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 1/physiology* ; Phosphorylation ; Protein Kinase C-alpha/metabolism* ; Wnt Proteins/metabolism* ; beta Catenin/metabolism*
Abstract
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 RORalpha-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKCalpha-dependent phosphorylation on serine residue 35 of RORalpha is crucial to link RORalpha to Wnt/beta-catenin signaling, which exerts inhibitory function of the expression of Wnt/beta-catenin target genes. Intriguingly, there is a significant correlation of reduction of RORalpha 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 RORalpha, functioning at the crossroads between the canonical and the noncanonical Wnt signaling pathways, in mediating transrepression of the Wnt/beta-catenin target genes, thereby providing new approaches for the development of therapeutic agents for human cancers.