Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression

Nat Commun. 2014 Aug 6;5:4619. doi: 10.1038/ncomms5619.

Abstract

Tumour-repopulating cells (TRCs) are a self-renewing, tumorigenic subpopulation of cancer cells critical in cancer progression. However, the underlying mechanisms of how TRCs maintain their self-renewing capability remain elusive. Here we show that relatively undifferentiated melanoma TRCs exhibit plasticity in Cdc42-mediated mechanical stiffening, histone 3 lysine residue 9 (H3K9) methylation, Sox2 expression and self-renewal capability. In contrast to differentiated melanoma cells, TRCs have a low level of H3K9 methylation that is unresponsive to matrix stiffness or applied forces. Silencing H3K9 methyltransferase G9a or SUV39h1 elevates the self-renewal capability of differentiated melanoma cells in a Sox2-dependent manner. Mechanistically, H3K9 methylation at the Sox2 promoter region inhibits Sox2 expression that is essential in maintaining self-renewal and tumorigenicity of TRCs both in vitro and in vivo. Taken together, our data suggest that 3D soft-fibrin-matrix-mediated cell softening, H3K9 demethylation and Sox2 gene expression are essential in regulating TRC self-renewal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biosensing Techniques
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Methylation
  • Disease Progression
  • Female
  • Fibrin / chemistry
  • Fluorescence Resonance Energy Transfer
  • Gene Silencing
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / chemistry*
  • Integrin beta1 / metabolism
  • Lysine / chemistry
  • Melanoma / metabolism*
  • Melanoma, Experimental
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Promoter Regions, Genetic
  • RNA, Small Interfering / metabolism
  • SOXB1 Transcription Factors / metabolism*
  • Skin Neoplasms / metabolism
  • Time Factors

Substances

  • Histones
  • Integrin beta1
  • RNA, Small Interfering
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Fibrin
  • Histone-Lysine N-Methyltransferase
  • Lysine