RETRACTED: KCTD1 Suppresses Canonical Wnt Signaling Pathway by Enhancing β-catenin Degradation (Retracted article. See vol. 17, 2022)

The canonical Wnt signaling pathway controls normal embryonic development, cellular proliferation and growth, and its aberrant activity results in human carcinogenesis. The core component in regulation of this pathway is beta-catenin, but molecular regulation mechanisms of beta-catenin stability are not completely known. Here, our recent studies have shown that KCTD1 strongly inhibits TCF/LEF reporter activity. Moreover, KCTD1 interacted with beta-catenin both in vivo by co-immunoprecipitation as well as in vitro through GST pull-down assays. We further mapped the interaction regions to the 1-9 armadillo repeats of beta-catenin and the BTB domain of KCTD1, especially Position Ala-30 and His-33. Immunofluorescence analysis indicated that KCTD1 promotes the cytoplasmic accumulation of beta-catenin. Furthermore, protein stability assays revealed that KCTD1 enhances the ubiquitination/degradation of beta-catenin in a concentration-dependent manner in HeLa cells. And the degradation of beta-catenin mediated by KCTD1 was alleviated by the proteasome inhibitor, MG132. In addition, KCTD1-mediated beta-catenin degradation was dependent on casein kinase 1 (CK1)-and glycogen synthase kinase-3 beta (GSK-3 beta)- mediated phosphorylation and enhanced by the E3 ubiquitin ligase beta-transducin repeat-containing protein (beta-TrCP). Moreover, KCTD1 suppressed the expression of endogenous Wnt downstream genes and transcription factor AP-2 alpha. Finally, we found that Wnt pathway member APC and tumor suppressor p53 influence KCTD1-mediated downregulation of beta-catenin. These results suggest that KCTD1 functions as a novel inhibitor of Wnt signaling pathway.