title: Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation.
abstract: The K+channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:β-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/β-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by β-catenin:T-cell factor (TCF)-4. In well-differentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with β-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of β-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped β-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of β-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/β-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis.
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.|Institut de Biologie Valrose (iBV), CNRS UMR7277, INSERM U1091, Bâtiment Sciences Naturelles, University of Nice Sophia Antipolis, Parc Valrose, F-06108 Nice, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Rapetti-Mauss
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Viviana
authors.initials: V
authors.lastname: Bustos
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Warren
authors.initials: W
authors.lastname: Thomas
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Jean
authors.initials: J
authors.lastname: McBryan
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Harry
authors.initials: H
authors.lastname: Harvey
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lajczak
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Madden
authors.affiliation: Institut de Biologie Valrose (iBV), CNRS UMR7277, INSERM U1091, Bâtiment Sciences Naturelles, University of Nice Sophia Antipolis, Parc Valrose, F-06108 Nice, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pellissier
authors.affiliation: Institut de Biologie Valrose (iBV), CNRS UMR7277, INSERM U1091, Bâtiment Sciences Naturelles, University of Nice Sophia Antipolis, Parc Valrose, F-06108 Nice, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Borgese
authors.affiliation: Institut de Biologie Valrose (iBV), CNRS UMR7277, INSERM U1091, Bâtiment Sciences Naturelles, University of Nice Sophia Antipolis, Parc Valrose, F-06108 Nice, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Soriani
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; bjpharvey@rcsi.ie.
authors.forename: Brian J
authors.identifier: 0000-0002-7388-8034
authors.initials: BJ
authors.lastname: Harvey
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011401:Promoter Regions, Genetic; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D051176:beta Catenin
keywords: KCNQ1; adherens junctions; colon cancer; epithelial–mesenchymal transition; β-catenin