Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response

Ruhul Amin (), Anjali Shukla, Jacqueline Jufen Zhu, Sohyoung Kim, Ping Wang, Simon Zhongyuan Tian, Andy D. Tran, Debasish Paul, Steven D. Cappell, Sandra Burkett, Huaitian Liu, Maxwell P. Lee, Michael J. Kruhlak, Jennifer E. Dwyer, R. Mark Simpson, Gordon L. Hager, Yijun Ruan and Kent W. Hunter ()
Additional contact information
Ruhul Amin: NIH
Anjali Shukla: NIH
Jacqueline Jufen Zhu: The Jackson Laboratory for Genomic Medicine
Sohyoung Kim: NIH
Ping Wang: The Jackson Laboratory for Genomic Medicine
Simon Zhongyuan Tian: The Jackson Laboratory for Genomic Medicine
Andy D. Tran: NIH
Debasish Paul: NIH
Steven D. Cappell: NIH
Sandra Burkett: NIH
Huaitian Liu: NIH
Maxwell P. Lee: NIH
Michael J. Kruhlak: NIH
Jennifer E. Dwyer: NIH
R. Mark Simpson: NIH
Gordon L. Hager: NIH
Yijun Ruan: The Jackson Laboratory for Genomic Medicine
Kent W. Hunter: NIH

Nature Communications, 2021, vol. 12, issue 1, 1-23

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27451-w

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DOI: 10.1038/s41467-021-27451-w

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