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

Y Tan, A Tajik, J Chen, Q Jia, F Chowdhury… - Nature …, 2014 - nature.com
Y Tan, A Tajik, J Chen, Q Jia, F Chowdhury, L Wang, J Chen, S Zhang, Y Hong, H Yi, DC Wu
Nature communications, 2014nature.com
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 …
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.
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