Targeting nuclear pore protein, NUP210, reduces metastasis through heterochromatin-mediated silencing of mechanosensitive genes

Amin, R.; Shukla, A.; Zhu, J. J.; Kim, S.; Wang, P.; Tian, S. Z.; Cappell, S. D.; Burkett, S.; Liu, H.; Lee, M. P.; Tran, A. D.; Kruhlak, M. J.; Hager, G. L.; Ruan, Y.; Hunter, K. W.

doi:10.1101/2020.02.05.936518

bioRxiv · 10.1101/2020.02.05.936518

Targeting nuclear pore protein, NUP210, reduces metastasis through heterochromatin-mediated silencing of mechanosensitive genes

Amin, R.·Shukla, A.·Zhu, J. J.·Kim, S.·Wang, P.·Tian, S. Z.·Cappell, S. D.·Burkett, S.·Liu, H.·Lee, M. P.·Tran, A. D.·Kruhlak, M. J.·Hager, G. L.·Ruan, Y.·Hunter, K. W.

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Abstract

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identified 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 a new insight into the role of nuclear pore protein in cellular mechanosensation and metastasis.

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Amin, R., Shukla, A., Zhu, J. J., Kim, S., Wang, P., Tian, S. Z., Cappell, S. D., Burkett, S., Liu, H., Lee, M. P., Tran, A. D., Kruhlak, M. J., Hager, G. L., Ruan, Y., Hunter, K. W.. 2020-02-06. Targeting nuclear pore protein, NUP210, reduces metastasis through heterochromatin-mediated silencing of mechanosensitive genes. https://doi.org/10.1101/2020.02.05.936518

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