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

ABSTRACT: Mechanical signals from the extracellular microenvironment have been shown to promote tumor and metastasis progression. It remains unclear how these signals are transmitted to the nucleus to regulate gene expression necessary for metastatic progression. In a genome-wide screen for metastasis-associated polymorphism in the non-coding regulatory region of the genome, we found NUP210, a nuclear pore complex protein as a metastasis susceptibility gene and a cellular mechanosensor. Depletion of NUP210 in metastatic cancer cells significantly reduces lung metastasis in mouse orthotopic transplantation models. Mechanistically, NUP210 interacts with histone H3.1/3.2 (preferentially enriched at the poised/bivalent gene promoters) at the nuclear periphery. To investigate how NUP210 regulates metastasis, we performed combined ChIP-seq and RNA-seq analysis to identify the NUP210-dependent downstream signaling pathways necessary for metastatic progression. Interestingly, RNA-seq analysis revealed that the loss of NUP210 in cancer cells significantly decreased the expression of mechanosensitive, cell adhesion/migration-related pro-metastatic genes. ChIP-seq analysis of H3K4me3 (transcriptional activation mark) and H3K27me3 (transcriptionally repressive, heterochromatin mark) in NUP210 WT/KO cells revealed that NUP210 loss resulted in increased heterochromatinization of mechanosensitive, cell migration-related genes associated at the nuclear periphery. Our results provide a new insight into the role of nuclear pore protein in regulating cellular mechanosensation and metastasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE146591 | GEO | 2021/03/05

REPOSITORIES: GEO

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Project description:Next-generation sequencing has revolutionized cancer biology by accelerating the unbiased discovery of novel mutations across human cancers. Transforming such discoveries into a conceptual framework of cancer progression requires narrowing the vast number of mutations down to the driver elements, and further reducing these to mutations that govern cancer progression as opposed to tumor initiation. By integrating next-generation RNA-sequencing (RNA-seq) with in vivo selection, we devise an approach that identifies a series of novel recurrent non-synonymous amino acid mutations that are enriched in metastatic breast cancer cells and predicted to significantly alter protein function. These mutations, found in PANX1, RBFA, REST, KRIT1 and ZSWIM6, are detected at higher frequencies in the transcriptomes of two patientsâ highly metastatic sub-lines relative to their poorly metastatic parental lines. We functionally characterize the cellular and molecular roles of one of these mutationsâa nonsense alteration that yields a truncated pannexin-1 (PANX11-89) plasma membrane megachannel subunitâin metastatic progression. PANX11-89 interacts with full-length PANX1 and augments PANX1 channel activity to promote the survival of cancer cells as they are mechanically deformed. Protection from deformation-induced cell death requires PANX1 channels to release ATP, which acts as a cell autonomous survival signal during mechanical stress. Functional characterization of additional nonsense and missense PANX1 mutations detected in epithelial cancers of the colon, lung, and prostate reveals that these mutants also enhance PANX1-mediated ATP release. In vivo testing of one such truncating mutation detected in a metastatic colorectal tumor also enhances early survival, dissemination and liver metastatic colonization by human colon cancer cells. Finally, pharmacological inhibition of PANX1 inhibits breast cancer metastasis, implicating PANX1 as a novel therapeutic target in cancer. Our findings reveal that ATP release through mechanosensitive PANX1 channels enables cancer cells to overcome a major metastasis suppressive barrier—deformation-induced death in the microvasculature. To systematically identify base-pair mutations present in metastatic cells that may drive cancer progression, we performed whole-transcriptome RNA-sequencing (RNA-seq) of in vivo-selected, highly metastatic human breast cancer cell sub-lines, CN-LM1A and MDA-LM2, as well as the CN34 and MDA-MB-231 parental lines from which they were derived. To minimize the false positive rate and allow for subsequent statistical analysis, we sequenced biological replicates of each cell line. Mutations conferring enhanced metastatic capacity should be enriched in the transcriptomes of highly metastatic cells relative to their less metastatic parental populations.

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

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