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Biochim Biophys Acta Mol Basis Dis. 2018 Jul;1864(7):2409-2419. doi: 10.1016/j.bbadis.2018.04.017. Epub 2018 Apr 21.

TRPM7 controls mesenchymal features of breast cancer cells by tensional regulation of SOX4.

Author information

1
Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
2
Institute for Bioengineering of Catalonia (IBEC), 08028 Barcelona, Spain; University of Barcelona, Barcelona 08028, Spain.
3
Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
4
Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
5
Institute for Bioengineering of Catalonia (IBEC), 08028 Barcelona, Spain; University of Barcelona, Barcelona 08028, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain; Centro de Investigación Biomédica en Red en Bioingeniería (CIBER), Biomateriales y Nanomedicina, Barcelona 08028, Spain.
6
Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: FrankN.vanLeeuwen@radboudumc.nl.

Abstract

Mechanically induced signaling pathways are important drivers of tumor progression. However, if and how mechanical signals affect metastasis or therapy response remains poorly understood. We previously found that the channel-kinase TRPM7, a regulator of cellular tension implicated in mechano-sensory processes, is required for breast cancer metastasis in vitro and in vivo. Here, we show that TRPM7 contributes to maintaining a mesenchymal phenotype in breast cancer cells by tensional regulation of the EMT transcription factor SOX4. The functional consequences of SOX4 knockdown closely mirror those produced by TRPM7 knockdown. By traction force measurements, we demonstrate that TRPM7 reduces cytoskeletal tension through inhibition of myosin II activity. Moreover, we show that SOX4 expression and downstream mesenchymal markers are inversely regulated by cytoskeletal tension and matrix rigidity. Overall, our results identify SOX4 as a transcription factor that is uniquely sensitive to cellular tension and indicate that TRPM7 may contribute to breast cancer progression by tensional regulation of SOX4.

KEYWORDS:

Cytoskeleton; Epithelial-mesenchymal transition; Mechanotransduction; SOX4; TRPM7

PMID:
29684587
DOI:
10.1016/j.bbadis.2018.04.017
[Indexed for MEDLINE]
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