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

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

Author information

1
1] Laboratory 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 [2] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [3].
2
1] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2].
3
1] Laboratory 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 [2].
4
Laboratory 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.
5
Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
6
Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
7
1] Laboratory 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 [2] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
8
1] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [3].
9
Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
10
1] Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Center for Biophysics and Computational Biology and Center for the Physics of Living Cells, Department of Physics, University of Illinois at Urbana-Champaign, Howard Hughs Medical Institute, Urbana, Illinois 61801, USA.
11
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
12
Department of Bioengineering and Institute of Engineering in Medicine, University of California-San Diego, La Jolla, California 92093, USA.
13
1] Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China [2] Department of Immunology, Institute of Basic Medical Sciences of Chinese Academy of Medical Sciences, Beijing 100005, China.

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.

PMID:
25099074
PMCID:
PMC4133791
DOI:
10.1038/ncomms5619
[Indexed for MEDLINE]
Free PMC Article

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