CDCP1 enhances Wnt signaling in colorectal cancer promoting nuclear localization of β-catenin and E-cadherin

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Abstract

Elevated CUB-domain containing protein 1 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival. While CDCP1 expression identifies stem cell populations that mediate lung metastasis, mechanisms underlying the role of this cell surface receptor in CRC have not been defined. We sought to identify CDCP1 regulated processes in CRC using stem cell populations, enriched from primary cells and cell lines, in extensive in vitro and in vivo assays. These experiments, demonstrating that CDCP1 is functionally important in CRC tumor initiation, growth and metastasis, identified CDCP1 as a positive regulator of Wnt signaling. Detailed cell fractionation, immunoprecipitation, microscopy, and immunohistochemical analyses demonstrated that CDCP1 promotes translocation of the key regulators of Wnt signaling, β-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated β-catenin and nuclear localized E-cadherin, increases sequestration of these proteins in cell membranes, disrupts regulation of CRC promoting genes, and reduces CRC tumor burden. Thus, disruption of CDCP1 perturbs pro-cancerous Wnt signaling including nuclear localization of β-catenin and E-cadherin.

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Acknowledgements

This work was funded by grant 2010–09 from the Wesley Research Institute to JWL and JDH, grants APP1021827 and APP1045801 from the Cancer Council Queensland, grant APP1121970 from the National Health and Medical Research Council to JDH, and Future Fellowship FT120100917 from the Australian Research Council to JDH, and NHMRC Early Career Fellowship 1091589 to MNA.

Author information

Conception and design were performed by YH and JDH. Acquisition of data was performed by YH, CMD, BSH, LH, YS, AB, TM, KB, LZ, AW, GM, SM, KYW, MNA, RCS, JSP, LJB, ADE, RL, AM, and BS. Administrative, technical and material support were provided by XZ, MM, DM and JWL. Data analysis and interpretation were performed by YH, LL, and JDH. Drafting of the manuscript was performed by YH, LL, and JDH, and all authors reviewed the manuscript.

Correspondence to John D. Hooper.

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