Bidirectional KCNQ1:?-catenin interaction drives colorectal cance.pdf (13.55 MB)
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Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation.

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posted on 22.11.2019 by Raphael Rapetti-Mauss, Viviana Bustos, Warren Thomas, Jean McBryan, Harry Harvey, Natalia Lajczak, Stephen F. Madden, Bernard Pellissier, Franck Borgese, Oliver Soriani, Brian J. Harvey

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 welldifferentiated 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.

Funding

National Biophotonics Imaging Platform Ireland. Higher Education Authority of Ireland.

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The original article is available at http://www.pnas.org

Published Citation

Rapetti-Mauss R, Bustos V, Thomas W, McBryan J, Harvey H, Lajczak N, Madden SF, Pellissier B, Borgese F, Soriani O, Harvey BJ. Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation. Proceedings of the National Academy of Sciences of the USA. 2017;114(16):4159-4164

Publication Date

01/04/2017

Publisher

National Academy of Sciences

PubMed ID

28373572

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