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

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 p...

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Detalles Bibliográficos
Autores principales: Tan, Youhua, Tajik, Arash, Chen, Junwei, Jia, Qiong, Chowdhury, Farhan, Wang, Lili, Chen, Junjian, Zhang, Shuang, Hong, Ying, Yi, Haiying, Wu, Douglas C., Zhang, Yuejin, Wei, Fuxiang, Poh, Yeh-Chuin, Seong, Jihye, Singh, Rishi, Lin, Li-Jung, Doğanay, Sultan, Li, Yong, Jia, Haibo, Ha, Taekjip, Wang, Yingxiao, Huang, Bo, Wang, Ning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133791/
https://www.ncbi.nlm.nih.gov/pubmed/25099074
http://dx.doi.org/10.1038/ncomms5619
Descripción
Sumario: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.