Jie Chen1,2, Jun Zhao2, Xuan Chen1, Chengming Ding1, Katie Lee2, Zeming Jia1, Yaoting Zhang1, Yuzheng Zhou3, Chaoying Wei3, Jiantai He1, Zanxian Xia3, Jian Peng1. 1. Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. 2. Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA. 3. State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, 410008, China.
Abstract
OBJECTIVE: Aberrant activation of Wnt/β-catenin signalling contributes significantly to the development of human colorectal cancers and β-catenin is the key signalling molecule transducing canonical Wnt/β-catenin signalling. Therefore, β-catenin is a promising therapeutic target for cancer treatment. This study demonstrates that the oncogenic IKKε kinase phosphorylates β-catenin to restrain its hyper activation, therefore promoting colorectal cancer (CRC) cell proliferation. MATERIALS AND METHODS: IKKε and β-catenin expression levels in human colorectal cancer tissues and cell lines were analysed by immunohistochemical staining and Western blotting. The regulation of IKKε on Wnt/β-catenin signalling pathway was studied by reporter assay and real-time PCR analysis in the context of IKKε stably knocking down. Co-immunoprecipitation was conducted to monitor the interaction between IKKε and β-catenin. Kinase assay was performed to measure β-catenin post-translational modifications induced by IKKε. RESULTS: Oncogenic IKKε kinase is required for the proliferation of colorectal cancer cells. Mechanistically, inhibition of IKKε results in β-catenin hyper activation and thwarts CRC cell proliferation. Furthermore, IKKε phosphorylates β-catenin and inhibits the activation of β-catenin signalling. CONCLUSION: Our study suggests that IKKε is a potential target to combat CRC induced by aberrant Wnt/β-catenin signalling.
OBJECTIVE: Aberrant activation of Wnt/β-catenin signalling contributes significantly to the development of humancolorectal cancers and β-catenin is the key signalling molecule transducing canonical Wnt/β-catenin signalling. Therefore, β-catenin is a promising therapeutic target for cancer treatment. This study demonstrates that the oncogenic IKKε kinase phosphorylates β-catenin to restrain its hyper activation, therefore promoting colorectal cancer (CRC) cell proliferation. MATERIALS AND METHODS: IKKε and β-catenin expression levels in humancolorectal cancer tissues and cell lines were analysed by immunohistochemical staining and Western blotting. The regulation of IKKε on Wnt/β-catenin signalling pathway was studied by reporter assay and real-time PCR analysis in the context of IKKε stably knocking down. Co-immunoprecipitation was conducted to monitor the interaction between IKKε and β-catenin. Kinase assay was performed to measure β-catenin post-translational modifications induced by IKKε. RESULTS: Oncogenic IKKε kinase is required for the proliferation of colorectal cancer cells. Mechanistically, inhibition of IKKε results in β-catenin hyper activation and thwarts CRC cell proliferation. Furthermore, IKKε phosphorylates β-catenin and inhibits the activation of β-catenin signalling. CONCLUSION: Our study suggests that IKKε is a potential target to combat CRC induced by aberrant Wnt/β-catenin signalling.
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