Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response.
Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response.
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DOI：
10.1038/s41467-021-27451-w
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发表时间：
2021-12-13
影响因子：
16.6
通讯作者：
Hunter KW
中科院分区：
文献类型：
--
作者：
Amin R;Shukla A;Zhu JJ;Kim S;Wang P;Tian SZ;Tran AD;Paul D;Cappell SD;Burkett S;Liu H;Lee MP;Kruhlak MJ;Dwyer JE;Simpson RM;Hager GL;Ruan Y;Hunter KW
来自细胞外微环境的机械信号与肿瘤和转移进展有关。在这里，我们发现核孔蛋白NUP210是人类雌激素受体阳性（ER+）乳腺癌的转移易感基因和细胞机械传感器。Nup210缺失抑制乳腺癌小鼠模型的肺转移。机制上，NUP210与连接细胞核和细胞骨架的LINC复合物蛋白SUN2相互作用。此外，NUP210/SUN2复合体通过BRD4和组蛋白H3.1/H3.2在核外周的短异构体与染色质相互作用。在Nup210敲除细胞中，机械敏感基因积累H3K27me3异染色质修饰，由多梳抑制复合体2介导，并在细胞核内差异重新定位。Nup210敲除细胞的转录抑制导致其转移能力所需的机械转导缺陷和局灶粘附。我们的研究提供了核孔蛋白在细胞机械感觉和转移中的重要作用。核孔蛋白在细胞力学感知和转移中的作用尚不清楚。在这里，作者发现核孔蛋白NUP210通过与机械传感器LINC复合体蛋白和染色质相互作用来调节机械敏感基因，从而促进转移。
Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identify nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides an important role of nuclear pore protein in cellular mechanosensation and metastasis. The involvement of nuclear pore proteins in cellular mechanosensing and metastasis is unclear. Here the authors identify that nuclear pore protein NUP210 promotes metastasis through the interaction with mechanotransducer LINC complex protein and chromatin to regulate mechanosensitive genes.
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影响因子：
50.3
作者：
Dravis C;Chung CY;Lytle NK;Herrera-Valdez J;Luna G;Trejo CL;Reya T;Wahl GM
通讯作者：
Wahl GM
影响因子：
2.5
作者：
Churchill, Gary A.;Gatti, Daniel M.;Munger, Steven C.;Svenson, Karen L.
通讯作者：
Svenson, Karen L.
影响因子：
11.2
作者：
Alsarraj J;Walker RC;Webster JD;Geiger TR;Crawford NP;Simpson RM;Ozato K;Hunter KW
通讯作者：
Hunter KW
影响因子：
30.5
作者：
Borlido J;Sakuma S;Raices M;Carrette F;Tinoco R;Bradley LM;D'Angelo MA
通讯作者：
D'Angelo MA
影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J