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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cytoskeleton / genetics
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Myosin Type II / genetics
  • Myosin Type II / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • SOXC Transcription Factors / genetics
  • SOXC Transcription Factors / metabolism*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*
  • Tensile Strength

Substances

  • Neoplasm Proteins
  • SOX4 protein, human
  • SOXC Transcription Factors
  • TRPM Cation Channels
  • Protein-Serine-Threonine Kinases
  • TRPM7 protein, human
  • Myosin Type II