Journal Article

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

Kruhlak, Michael J., Liu, Huaitian, Lee, Maxwell P., Hunter, Kent W., Zhu, Jacqueline Jufen, Amin, Ruhul, Cappell, Steven D., Dwyer, Jennifer E., Ruan, Yijun, Shukla, Anjali, Wang, Ping, Tian, Simon Zhongyuan, Tran, Andy D., Burkett, Sandra, Kim, Sohyoung, Simpson, R. Mark, Hager, Gordon L., Paul, Debasish

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/105 / 13/106 / 13/109 / 13/31 / 13/51 / 13/89 / 14/19 / 14/32 / 38 / 38/23 / 38/90 / 45/41 / 45/44 / 45/88 / 631/67/1347 / 64/60 / 692/4028/67/1347 / 82/51 / 96 / 96/21 / 96/35 / Animal models / Animals / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / CCCTC-Binding Factor - metabolism / Cell Line, Tumor / Cell Movement - genetics / Chromatin / Cytoskeleton / Cytoskeleton - metabolism / Depletion / Enhancer of Zeste Homolog 2 Protein - metabolism / Estrogen receptors / Estrogens / Focal Adhesions - genetics / Gene Expression Regulation, Neoplastic / Gene silencing / Genes / Heterochromatin / Heterochromatin - metabolism / Histone H3 / Histones / Histones - metabolism / Humanities and Social Sciences / Humans / Lung cancer / Mechanical analysis / Mechanical stimuli / Mechanotransduction / Mechanotransduction, Cellular - genetics / Metastases / Metastasis / Methyltransferases - metabolism / Mice / Microenvironments / multidisciplinary / Neoplasm Metastasis / Neoplastic Cells, Circulating - metabolism / Nuclear Envelope - metabolism / Nuclear Pore Complex Proteins - genetics / Nuclear Pore Complex Proteins - metabolism / Nuclear Proteins - metabolism / Nuclei (cytology) / Polycomb group proteins / Polymorphism, Genetic / Prognosis / Promoter Regions, Genetic / Protein Binding / Proteins / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Transcription Factors - metabolism / Tumor Microenvironment / Tumors