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

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

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Version 1 2019-11-22, 16:43
journal contribution
posted on 2019-11-22, 16:43 authored 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.

History

Comments

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

2017-04-01

Publisher

National Academy of Sciences

PubMed ID

28373572

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