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 Doǧanay, Yong Li, Haibo JiaTaekjip Ha, Yingxiao Wang, Bo Huang, Ning Wang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number4619
JournalNature Communications
Volume5
DOIs
StatePublished - Aug 6 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Tan, Y., Tajik, A., Chen, J., Jia, Q., Chowdhury, F., Wang, L., Chen, J., Zhang, S., Hong, Y., Yi, H., Wu, D. C., Zhang, Y., Wei, F., Poh, Y. C., Seong, J., Singh, R., Lin, L. J., Doǧanay, S., Li, Y., ... Wang, N. (2014). Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression. Nature Communications, 5, [4619]. https://doi.org/10.1038/ncomms5619