The CK1δ/ε-Tip60 Axis Enhances Wnt/β-Catenin Signaling via Regulating β-Catenin Acetylation in Colon Cancer

Casein kinase 1 delta/epsilon (CK1 delta/epsilon) are well-established positive modulators of the Wnt/beta-catenin signaling pathway. However, the molecular mechanisms involved in the regulation of beta-catenin transcriptional activity by CK1 delta/epsilon remain unclear. In this study, we found that CK1 delta/epsilon could enhance beta-catenin-mediated transcription through regulating beta-catenin acetylation. CK1 delta/epsilon interacted with Tip60 and facilitated the recruitment of Tip60 to beta-catenin complex, resulting in increasing beta-catenin acetylation at K49. Importantly, Tip60 significantly enhanced the SuperTopFlash reporter activity induced by CK1 delta/epsilon or/and beta-catenin. Furthermore, a CK1 delta/CK1 epsilon/beta-catenin/Tip60 complex was detected in colon cancer cells. Simultaneous knockdown of CK1 delta and CK1 epsilon significantly attenuated the interaction between beta-catenin and Tip60. Notably, inhibition of CK1 delta/epsilon or Tip60, with shRNA or small molecular inhibitors downregulated the level of beta-catenin acetylation at K49 in colon cancer cells. Finally, combined treatment with CK1 inhibitor SR3029 and Tip60 inhibitor MG149 had more potent inhibitory effect on beta-catenin acetylation, the transcription of Wnt target genes and the viability and proliferation in colon cancer cells. Taken together, our results revealed that the transcriptional activity of beta-catenin could be modulated by the CK1 delta/epsilon-beta-catenin-Tip60 axis, which may be a potential therapeutic target for colon cancer.

Automated summary

CK1 delta/epsilon enhance beta-catenin-mediated transcription by regulating beta-catenin acetylation. CK1 delta/epsilon interact with Tip60 and facilitate its recruitment to the beta-catenin complex, leading to increased beta-catenin acetylation at K49. Furthermore, this study discovers that a complex consisting of CK1 delta/CK1 epsilon/beta-catenin/Tip60 is present in colon cancer cells, and this complex plays an important role in beta-catenin acetylation.