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Soft matrices downregulate FAK activity to promote growth of tumor-repopulating cells

Youhua Tan1, Adam Richard Wood2, Qiong Jia3

  • 1Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China; Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA; Interdisciplinary Division of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Kowloon, Hong Kong SAR, China.

Biochemical and Biophysical Research Communications
|December 24, 2016
PubMed

Insights

Soft matrices promote cancer growth by reducing focal adhesion kinase (FAK), which lowers histone 3 lysine 9 (H3K9) methylation, enhancing tumor-repopulating cells (TRCs) proliferation.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Biochemistry

Background:

  • Tumor-repopulating cells (TRCs) drive tumor growth.
  • Soft matrices promote TRC growth via histone 3 lysine 9 (H3K9) demethylation and Sox2 expression.
  • The mechanism linking soft matrices to H3K9 demethylation is unclear.

Purpose of the Study:

  • Investigate the mechanism by which soft matrices induce H3K9 demethylation.
  • Elucidate the role of focal adhesion kinase (FAK), Cdc42, and RhoA in this process.
  • Determine how these factors influence TRC proliferation and Sox2 expression in different matrix stiffnesses.

Main Methods:

  • Comparing FAK and H3K9 methylation levels in TRCs on soft matrices versus control cells on rigid substrates.
  • Manipulating FAK, Cdc42, and RhoA expression (silencing or overexpression) in melanoma cells.
  • Assessing Sox2 expression and cell proliferation in response to genetic modifications and matrix stiffness.

Main Results:

  • TRCs show lower FAK and H3K9 methylation in soft matrices.
  • FAK manipulation inversely affects H3K9 methylation.
  • Cdc42/RhoA can restore H3K9 methylation in FAK-knockdown cells.
  • Silencing FAK, Cdc42, or RhoA promotes proliferation in stiff matrices, while overexpression inhibits TRC growth in soft matrices.

Conclusions:

  • Soft matrices reduce FAK, leading to decreased Cdc42/RhoA and H3K9 methylation.
  • This pathway promotes TRC growth and Sox2 expression.
  • Targeting FAK, Cdc42, or RhoA may offer therapeutic strategies for TRC-driven cancers.
Keywords:
CancerFocal adhesion kinaseGrowthMatrix stiffnessTumor repopulating cell

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