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.
Bibliographical noteFunding Information:
For the analysis of phosphorylated RORα and PKCα expression in human tissue samples, 30 paired fresh frozen colon cancer tissues and matched normal mucosa tissues were selected. The frozen fresh human tissue specimens were supplied from the Liver Cancer Specimen Bank supported by National Research Resource Bank Program of the Korea Science and Engineering Foundation in the Ministry of Science and Technology. The consents to use the tissue specimens for research purposes were obtained from patients, and the utilization of the specimens for this research was authorized by the Institutional Review Board of College of Medicine, Yonsei University.
pCMX-RORα expression plasmid was kindly provided by V. Giguère, and various PKC constructs were provided by J.-W. Soh. We thank K. Han, M.H. Kim, and S.-I. Kim for technical assistance and discussion. This work was supported by Creative Research Initiatives program (Research Center for Chromatin Dynamics, 2009-0081563) to S.H.B.; the SRC program (R11-2005-017-04004-0) and the Ubiquitome Research Program (2008-00983) to K.I.K. from the National Research Foundation (NRF) grant funded by the Ministry of Education, Science, and Technology (MEST) of Korea; and by Brain Korea 21 fellowship to J.M.L., I.S.K., Hyunkyung Kim, J.S.L., K.K., J.J., and H.Y.Y.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology