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Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):4159-4164. doi: 10.1073/pnas.1702913114. Epub 2017 Apr 3.

Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation.

Author information

1
Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
2
Institut de Biologie Valrose (iBV), CNRS UMR7277, INSERM U1091, Bâtiment Sciences Naturelles, University of Nice Sophia Antipolis, Parc Valrose, F-06108 Nice, France.
3
Department of Molecular Medicine, Royal College of Surgeons in Ireland (RCSI) Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; bjpharvey@rcsi.ie.

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.

KEYWORDS:

KCNQ1; adherens junctions; colon cancer; epithelial–mesenchymal transition; β-catenin

PMID:
28373572
PMCID:
PMC5402468
DOI:
10.1073/pnas.1702913114
[Indexed for MEDLINE]
Free PMC Article

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