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.
Highlights
Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression
To identify polymorphic accessible chromatin regions associated with metastatic colonization, benzonaseaccessible chromatin (BACh) analysis was performed on isogenic cell lines derived from the spontaneous mammary tumor of BALB/cJ mice (67NR, 4T07, and 4T1)[15] (Fig. 1a)
The resulting gene list was filtered through expression data of mice resulting from a cross between the MMTV-PyMT model[18] and the Diversity Outbred (DO) to identify genes associated with metastasis in this population
Summary
Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Changes in chromatin accessibility[8] or disruptions of large heterochromatin domains[9] can result in alteration of transcriptional programs that enable tumor cells to acquire metastatic phenotypes In addition to these changes, previously our laboratory has demonstrated that inherited polymorphisms have a significant effect on metastatic capacity[10]. To gain further understanding of how polymorphisms affect regulatory elements and the subsequent metastatic phenotype, in this study, we have integrated chromatin accessibility and longrange chromatin interaction analysis to identify potential metastasis susceptibility genes with polymorphic promoters and/ or distant enhancers. This analysis identified Nup[210], a gene encoding a nuclear pore complex (NPC) protein, as a potential metastasis susceptibility gene. We established that NUP210 is responsive to mechanical signals of the extracellular microenvironment and promotes lung metastasis in mouse models of breast cancer through alteration of the mechanical response, focal adhesion, and cell migration in a nucleocytoplasmic transport-independent manner
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