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 Jia; Taekjip Ha; Yingxiao Wang; Bo Huang; Ning Wang

doi:10.1038/ncomms5619

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 journal › Article › peer-review

99 Scopus citations

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 language	English (US)
Article number	4619
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5619
State	Published - Aug 6 2014
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms5619

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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, Article 4619. https://doi.org/10.1038/ncomms5619

Tan, Y, Tajik, A, Chen, J, Jia, Q, Chowdhury, F, Wang, L, Chen, J, Zhang, S, Hong, Y, Yi, H, Wu, DC, Zhang, Y, Wei, F, Poh, YC, Seong, J, Singh, R, Lin, LJ, Doǧanay, S, Li, Y, Jia, H, Ha, T, Wang, Y, Huang, B & Wang, N 2014, 'Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression', Nature communications, vol. 5, 4619. https://doi.org/10.1038/ncomms5619

@article{4a1b8d6b6ef243c8bd9c4ffcc02e7f7d,

title = "Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression",

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.",

author = "Youhua Tan and Arash Tajik and Junwei Chen and Qiong Jia and Farhan Chowdhury and Lili Wang and Junjian Chen and Shuang Zhang and Ying Hong and Haiying Yi and Wu, {Douglas C.} and Yuejin Zhang and Fuxiang Wei and Poh, {Yeh Chuin} and Jihye Seong and Rishi Singh and Lin, {Li Jung} and Sultan Doǧanay and Yong Li and Haibo Jia and Taekjip Ha and Yingxiao Wang and Bo Huang and Ning Wang",

note = "Funding Information: We thank Wenting Yao for help. We thank Dr Alice Ting for help with the H3K9 FRET biosensor. We thank Dr Fei Wang and his lab at UIUC for assistance. This work was supported by the funds from Huazhong University of Science and Technology and US NIH grant GM 072744 (to N.W.) and National Science Foundation through the Physics Frontiers Center Program (0822613) (to T.H.). T.H. is an investigator with the Howard Hughes Medical Institute. A.T. acknowledges partial financial support from Natural Sciences and Engineering Research Council (NSERC) of Canada through PGS Doctoral Scholarship. F.C. acknowledges support from IGB fellowship at UIUC.",

year = "2014",

month = aug,

day = "6",

doi = "10.1038/ncomms5619",

language = "English (US)",

volume = "5",

journal = "Nature communications",

issn = "2041-1723",

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T1 - Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression

AU - Tan, Youhua

AU - Tajik, Arash

AU - Chen, Junwei

AU - Jia, Qiong

AU - Chowdhury, Farhan

AU - Wang, Lili

AU - Chen, Junjian

AU - Zhang, Shuang

AU - Hong, Ying

AU - Yi, Haiying

AU - Wu, Douglas C.

AU - Zhang, Yuejin

AU - Wei, Fuxiang

AU - Poh, Yeh Chuin

AU - Seong, Jihye

AU - Singh, Rishi

AU - Lin, Li Jung

AU - Doǧanay, Sultan

AU - Li, Yong

AU - Jia, Haibo

AU - Ha, Taekjip

AU - Wang, Yingxiao

AU - Huang, Bo

AU - Wang, Ning

N1 - Funding Information: We thank Wenting Yao for help. We thank Dr Alice Ting for help with the H3K9 FRET biosensor. We thank Dr Fei Wang and his lab at UIUC for assistance. This work was supported by the funds from Huazhong University of Science and Technology and US NIH grant GM 072744 (to N.W.) and National Science Foundation through the Physics Frontiers Center Program (0822613) (to T.H.). T.H. is an investigator with the Howard Hughes Medical Institute. A.T. acknowledges partial financial support from Natural Sciences and Engineering Research Council (NSERC) of Canada through PGS Doctoral Scholarship. F.C. acknowledges support from IGB fellowship at UIUC.

PY - 2014/8/6

Y1 - 2014/8/6

N2 - 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.

AB - 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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JO - Nature communications

JF - Nature communications

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ER -

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

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