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.
authors.affiliation: 1] Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China [2] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [3].
authors.forename: Youhua
authors.initials: Y
authors.lastname: Tan
authors.affiliation: 1] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2].
authors.forename: Arash
authors.initials: A
authors.lastname: Tajik
authors.affiliation: 1] Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China [2].
authors.forename: Junwei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Farhan
authors.initials: F
authors.lastname: Chowdhury
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Junjian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Yi
authors.affiliation: Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Wei
authors.affiliation: 1] Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China [2] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Yeh-Chuin
authors.initials: YC
authors.lastname: Poh
authors.affiliation: 1] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [3].
authors.forename: Jihye
authors.initials: J
authors.lastname: Seong
authors.affiliation: Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Rishi
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Li-Jung
authors.initials: LJ
authors.lastname: Lin
authors.affiliation: 1] Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Center for Biophysics and Computational Biology and Center for the Physics of Living Cells, Department of Physics, University of Illinois at Urbana-Champaign, Howard Hughs Medical Institute, Urbana, Illinois 61801, USA.
authors.forename: Sultan
authors.initials: S
authors.lastname: Doğanay
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Jia
authors.affiliation: 1] Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Center for Biophysics and Computational Biology and Center for the Physics of Living Cells, Department of Physics, University of Illinois at Urbana-Champaign, Howard Hughs Medical Institute, Urbana, Illinois 61801, USA.
authors.forename: Taekjip
authors.initials: T
authors.lastname: Ha
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California-San Diego, La Jolla, California 92093, USA.
authors.forename: Yingxiao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China [2] Department of Immunology, Institute of Basic Medical Sciences of Chinese Academy of Medical Sciences, Beijing 100005, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.affiliation: 1] Laboratory for Cell Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China [2] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
mesh_terms: D000818:Animals; D015374:Biosensing Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D005337:Fibrin / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry*; D019012:Integrin beta1 / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D008545:Melanoma / Q000378:metabolism*; D008546:Melanoma, Experimental; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism; D013997:Time Factors
chemical_list: D006657:Histones; D019012:Integrin beta1; D034741:RNA, Small Interfering; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D005337:Fibrin; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine
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