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- Title
Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response.
- Authors
Amin, Ruhul; Shukla, Anjali; Zhu, Jacqueline Jufen; Kim, Sohyoung; Wang, Ping; Tian, Simon Zhongyuan; Tran, Andy D.; Paul, Debasish; Cappell, Steven D.; Burkett, Sandra; Liu, Huaitian; Lee, Maxwell P.; Kruhlak, Michael J.; Dwyer, Jennifer E.; Simpson, R. Mark; Hager, Gordon L.; Ruan, Yijun; Hunter, Kent W.
- Abstract
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.
- Subjects
NUCLEAR proteins; METASTASIS; BREAST cancer; LABORATORY mice; ESTROGEN receptors
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-27451-w