Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. It remains unclear how these mechanical signals are transmitted to the cell nucleus to regulate gene expression in metastasis. In an attempt to characterize metastasis-associated polymorphisms in the non-coding regulatory regions of the genome, we identified nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Polymorphisms in the mouse Nup210 promoter affect Nup210 transcription via alteration of CTCF binding. Depletion of Nup210 reduces lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with histone H3.1/H3.2 at the nuclear periphery and prevents its heterochromatin (H3K27me3) modification to regulate mechanosensitive, metastasis- promoting gene expression. Upon Nup210 knockout, these mechanosensitive genes are differentially repositioned and become repressed due to heterochromatinization. As a result, Nup210 depletion decreases mechanotransduction and focal adhesion in vitro and circulating tumor cells in vivo. Our study provides a new insight into the role of nuclear pore protein in cellular mechanosensation and metastasis.

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