Nuclear pore complex protein, Nup210 is a novel mediator of metastasis in breast cancer

Authors

• R Amin
• A Shukla
• S Kim
• J Zhu
• Y Ruan
• G Hager
• K Hunter

Abstract

Majority of cancer-related death are due to distant organ metastasis, not due to primary tumor. Previously we demonstrated that genetic background in transcriptional regulator regions influences the metastatic outcome in breast cancer. To focus on genes associated with the colonization step of metastasis, we have mapped accessible chromatin sites in two isogenic mouse mammary tumor cell lines, 4T07 and 4T1. 4TO7 disseminates from orthotopic tumors but does not form macroscopic metastases. In contrast, the 4T1 cell line completes the metastatic process. Differences in accessible chromatin are therefore likely to be enriched for genes associated with colonization. Polymorphisms from high- and low-metastasis susceptible mouse strains were then mapped onto the accessible chromatin sites to identify genes with polymorphic promoters putatively associated with the metastatic outcome. This screen identified nuclear pore complex protein, Nup210 as a potential metastatic susceptibility gene. Nup210 knockout in metastatic mouse mammary tumor cell lines revealed that Nup210-depletion significantly decreased lung metastases in mice. Conversely, overexpression of Nup210 increased lung metastasis. In addition, mice injected with Nup210-depleted cancer cells exhibit fewer circulating tumor cells (CTC), a key intermediate of metastatic dissemination. Mechanistically, Nup210-depleted cells lose focal adhesion, a process critical for cell migration, invasion and metastasis. Mass spectrometry analysis demonstrates that Nup210 interacts with histone H3 variants associated at the nuclear periphery. ChIP-seq analysis revealed that loss of Nup210 erased H3K4me3 transcriptional activation mark from the promoter of cell adhesion and migration genes. Given the role of nuclear pore complex proteins in general nucleocytoplasmic transport, our study revealed a novel role of Nup210 in promoting metastasis.

Scientific Focus Area: Cancer Biology

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