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

ABSTRACT

Casein kinase 1δ/ϵ (CK1δ/ϵ) are well-established positive modulators of the Wnt/ß-catenin signaling pathway. However, the molecular mechanisms involved in the regulation of ß-catenin transcriptional activity by CK1δ/ϵ remain unclear. In this study, we found that CK1δ/ϵ could enhance ß-catenin-mediated transcription through regulating ß-catenin acetylation. CK1δ/ϵ interacted with Tip60 and facilitated the recruitment of Tip60 to ß-catenin complex, resulting in increasing ß-catenin acetylation at K49. Importantly, Tip60 significantly enhanced the SuperTopFlash reporter activity induced by CK1δ/ϵ or/and ß-catenin. Furthermore, a CK1δ/CK1ϵ/ß-catenin/Tip60 complex was detected in colon cancer cells. Simultaneous knockdown of CK1δ and CK1ϵ significantly attenuated the interaction between ß-catenin and Tip60. Notably, inhibition of CK1δ/ϵ or Tip60, with shRNA or small molecular inhibitors downregulated the level of ß-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 ß-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 ß-catenin could be modulated by the CK1δ/ϵ-ß-catenin-Tip60 axis, which may be a potential therapeutic target for colon cancer.