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

Youhua Tan, Arash Tajik, Junwei Chen, Qiong Jia, Farhan Chowdhury, Lili Wang, Junjian Chen, Shuang Zhang, Ying Hong, Haiying Yi, Douglas C. Wu, Yuejin Zhang, Fuxiang Wei, Yeh-Chuin Poh, Jihye Seong, Rishi Singh, Li-Jung Lin, Sultan Doğanay, Yong Li, Haibo Jia, Taekjip Ha, Yingxiao Wang, Bo Huang and Ning Wang ()
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Youhua Tan: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Arash Tajik: College of Engineering, University of Illinois at Urbana–Champaign
Junwei Chen: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Qiong Jia: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Farhan Chowdhury: Institute for Genomic Biology, University of Illinois at Urbana–Champaign
Lili Wang: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Junjian Chen: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Shuang Zhang: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Ying Hong: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Haiying Yi: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Douglas C. Wu: College of Engineering, University of Illinois at Urbana–Champaign
Yuejin Zhang: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Fuxiang Wei: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Yeh-Chuin Poh: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Jihye Seong: College of Engineering, University of Illinois at Urbana–Champaign
Rishi Singh: College of Engineering, University of Illinois at Urbana–Champaign
Li-Jung Lin: University of Illinois at Urbana–Champaign
Sultan Doğanay: Institute for Genomic Biology, University of Illinois at Urbana–Champaign
Yong Li: Tongji Medical College, Huazhong University of Science and Technology
Haibo Jia: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology
Taekjip Ha: Institute for Genomic Biology, University of Illinois at Urbana–Champaign
Yingxiao Wang: University of California–San Diego
Bo Huang: Tongji Medical College, Huazhong University of Science and Technology
Ning Wang: Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5619

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