基质柔软度通过H3K9去甲基化和Sox2表达调节肿瘤再增殖细胞的可塑性。
Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression.
作者信息
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
机构信息
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].
1] Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2].
出版信息
Nat Commun. 2014 Aug 6;5:4619. doi: 10.1038/ncomms5619.
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.
肿瘤再增殖细胞（TRCs）是癌细胞中具有自我更新能力和致瘤性的亚群，在癌症进展中起关键作用。然而，TRCs维持其自我更新能力的潜在机制仍不清楚。在此，我们表明相对未分化的黑色素瘤TRCs在Cdc42介导的机械硬化、组蛋白3赖氨酸残基9（H3K9）甲基化、Sox2表达和自我更新能力方面表现出可塑性。与分化的黑色素瘤细胞相比，TRCs的H3K9甲基化水平较低，对基质硬度或施加的力无反应。沉默H3K9甲基转移酶G9a或SUV39h1以Sox2依赖的方式提高分化的黑色素瘤细胞的自我更新能力。从机制上讲，Sox2启动子区域的H3K9甲基化抑制Sox2表达，而Sox2表达对于在体外和体内维持TRCs的自我更新和致瘤性至关重要。综上所述，我们的数据表明3D软纤维蛋白基质介导的细胞软化、H3K9去甲基化和Sox2基因表达对于调节TRC自我更新至关重要。
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