Hyper activation of β-catenin signalling induced by IKKε inhibition thwarts colorectal cancer cell proliferation.

Objective: Aberrant activation of Wnt/beta-catenin signalling contributes significantly to the development of human colorectal cancers and beta-catenin is the key signalling molecule transducing canonical Wnt/beta-catenin signalling. Therefore, beta-catenin is a promising therapeutic target for cancer treatment. This study demonstrates that the oncogenic IKKe kinase phosphorylates beta-catenin to restrain its hyper activation, therefore promoting colorectal cancer (CRC) cell proliferation. Materials and methods: IKKe and beta-catenin expression levels in human colorectal cancer tissues and cell lines were analysed by immunohistochemical staining and Western blotting. The regulation of IKKe on Wnt/beta-catenin signalling pathway was studied by reporter assay and real-ime PCR analysis in the context of IKKe stably knocking down. Co-immunoprecipitation was conducted to monitor the interaction between IKKe and beta-catenin. Kinase assay was performed to measure beta-catenin post-translational modifications induced by IKKe. Results: Oncogenic IKKe kinase is required for the proliferation of colorectal cancer cells. Mechanistically, inhibition of IKKe results in beta-catenin hyper activation and thwarts CRC cell proliferation. Furthermore, IKKe phosphorylates beta-catenin and inhibits the activation of beta-catenin signalling. Conclusion: Our study suggests that IKKe is a potential target to combat CRC induced by aberrant Wnt/beta-catenin signalling.