FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion

PLoS One. 2013 Sep 26;8(9):e74923. doi: 10.1371/journal.pone.0074923. eCollection 2013.

Abstract

Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Line, Tumor
  • Cell Movement / genetics*
  • Cell Shape
  • Endothelium / metabolism
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Fetal Proteins / genetics
  • Fetal Proteins / metabolism*
  • Formins
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Gene Silencing
  • Humans
  • Mesoderm / pathology
  • Mouth Neoplasms / enzymology
  • Mouth Neoplasms / genetics*
  • Mouth Neoplasms / pathology*
  • Neoplasm Invasiveness
  • Neoplasms, Squamous Cell / enzymology
  • Neoplasms, Squamous Cell / genetics
  • Neoplasms, Squamous Cell / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plasma Cells / metabolism
  • Proteolysis
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • Transcriptome / genetics
  • Up-Regulation / genetics*

Substances

  • FHOD1 protein, human
  • Fetal Proteins
  • Formins
  • Nuclear Proteins
  • RNA, Small Interfering

Grant support

This research was supported by funding from The Academy of Finland, Finska Läkaresällskapet, Sigrid Juselius Foundation, K Albin Johansson Foundation, The Finnish Cancer Organizations and Turku University Hospital Research Funds. Maria Gardberg is a Ph.D. student supported by the National Graduate School of Clinical Investigation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.