Systems genomics of nucleoporins provides prognostic insights into breast cancer
Abstract
Background: Nucleoporins (Nups) constitute a large group of proteins that are structurally arranged at the nuclear envelope and facilitate the bidirectional movement of molecules across the nuclear membrane. In addition to regulating the shuttling of ribonucleoprotein complexes, RNAs and proteins, various Nups interact with chromatin either directly or indirectly, thus regulating gene expression. Any mutations or expression anomalies of Nups may lead to abnormal localization of critical molecules, or dysregulated expression of genes that they interact with. A comprehensive genomic study encompassing all Nup genes in relation to breast cancer is lacking.
Methods: We used genomic and transcriptomic datasets from Pan-Cancer TCGA (The Cancer Genome Atlas), Genotype-Tissue Expression (GTEx) and microarray platforms and conducted in silico analysis of all the genes encoding nucleoporins that are associated with the Nuclear Pore Complexes (NPCs). For mutation detection, we used cBioportal; for expression analysis, we used Xena and for patient survival plots, KMPlot was utilized.
Results: The genetic and molecular profile of nucleoporin genes identified multiple mutations and detected aberrant expression in breast cancer. Interestingly, NUP133, AHCTF1, TPR, Nup121L showed simultaneous gene amplification in nearly 10% of breast cancer patients. In addition, deregulated expression of some of the nucleoporins, namely, NUP62, NUP 93, NUP98, NUP155, POM121L12, RAE1, SEC13, TPR were correlated with patient prognosis.
Conclusion: The current study is the first one that unravels a comprehensive molecular and genetic profile of nucleoporins genes in breast cancer and underscores the critical roles of various nucleoporins in cancer progression. The identified molecules may advance our understanding of the etiology of the disease and serve as possible targets for novel therapeutic strategies in cancer.
Keywords: Nuclear Pore Complexes (NPCs); Nucleoporins; Breast cancer; Bioinformatics
Full Text:
PDFReferences
Paci G, Caria J, Lemke EA. Cargo transport through the nuclear pore complex at a glance. Journal of Cell Science, (2021); 134(2): jcs247874.
Fernandez-Martinez J, Rout MP. One Ring to Rule them All? Structural and Functional Diversity in the Nuclear Pore Complex. Trends in Biochemical Sciences, (2021); 46(7): 595-607.
Hurt E, Beck M. Towards understanding nuclear pore complex architecture and dynamics in the age of integrative structural analysis. Trends in Biochemical Sciences, (2015); 34: 31-8.
Sakiyama Y, Panatala R, Lim RYH. Structural dynamics of the nuclear pore complex. Seminars in Cell & Developmental Biology, (2017); 68: 27-33.
Souquet B, Freed E, Berto A, Andric V, Audugé N, Reina-San-Martin B, Lacy E, Doye V. Nup133 Is Required for Proper Nuclear Pore Basket Assembly and Dynamics in Embryonic Stem Cells. Cell Reports, (2018); 23(8): 2443-2454.
Strawn LA, Shen T, Shulga N, Goldfarb DS, Wente SR. Minimal nuclear pore complexes define FG repeat domains essential for transport. Nature Cell Biology, (2004); 6(3): 197-206.
Cook A, Bono F, Jinek M, Conti E. Structural biology of nucleocytoplasmic transport. Annual Review of Biochemistry, (2007); 76: 647-71.
Güttler T, Görlich D. Ran-dependent nuclear export mediators: a structural perspective. The EMBO Journal, (2011); 30(17): 3457-74.
Rougemaille M, Dieppois G, Kisseleva-Romanova E, Gudipati RK, Lemoine S, et al. THO/Sub2p functions to coordinate 3'-end processing with gene-nuclear pore association. Cell, (2008); 135(2): 308-21.
Taddei A, Van Houwe G, Hediger F, Kalck V, Cubizolles F, et al. Nuclear pore association confers optimal expression levels for an inducible yeast gene. Nature, (2006); 441(7094): 774-8.
Light WH, Brickner DG, Brand VR, Brickner JH. Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memory. Molecular Cell, (2010); 40(1): 112-25.
Brickner DG, Brickner JH. Interchromosomal clustering of active genes at the nuclear pore complex. Nucleus, (2012); 3(6): 487-92.
Casolari JM, Brown CR, Komili S, West J, Hieronymus H, et al. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell, (2004); 117(4): 427-39.
Brown CR, Silver PA. Transcriptional regulation at the nuclear pore complex. Current Opinion in Genetics & Development, (2007); 17(2): 100-6.
Vaquerizas JM, Suyama R, Kind J, Miura K, Luscombe NM, et al. Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genome. PLOS Genetics, (2010); 6(2): e1000846.
Kuhn TM, Capelson M. Nuclear Pore Proteins in Regulation of Chromatin State. Cells, (2019); 8(11): 1414.
Ibarra A, Benner C, Tyagi S, Cool J, Hetzer MW. Nucleoporin-mediated regulation of cell identity genes. Genes & Development, (2016); 30(20): 2253-2258.
Sun J, Shi Y, Yildirim E. The Nuclear Pore Complex in Cell Type-Specific Chromatin Structure and Gene Regulation. Trends in Genetics, (2019); 35(8): 579-588.
Sajidah ES, Lim K, Wong RW. How SARS-CoV-2 and Other Viruses Build an Invasion Route to Hijack the Host Nucleocyto-plasmic Trafficking System. Cells, (2021); 10(6): 1424.
Shen Q, Wang YE, Palazzo AF. Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection. Journal of Biological Chemistry, (2021); 297(1): 100856.
Burdine RD, Preston CC, Leonard RJ, Bradley TA, Faustino RS. Nucleoporins in cardiovascular disease. Journal of Molecular and Cellular Cardiology, (2020); 141: 43-52.
Oka M, Mura S, Otani M, Miyamoto Y, Nogami J, et al. Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells. Elife, (2019); 8: e46667.
Fahrenkrog B. Nucleoporin Gene Fusions and Hematopoietic Malignancies. New Journal of Science, (2014); 18
Nofrini V, Di Giacomo D, Mecucci C. Nucleoporin genes in human diseases. European Journal of Human Genetics, (2016); 24(10): 1388-95.
Chow KH, Factor RE, Ullman KS. The nuclear envelope environment and its cancer connections. Nature Reviews Cancer, (2012); 12(3):v196-209.
Simon DN, Rout MP. Cancer and the nuclear pore complex. Advances in Experimental Medicine and Biology, (2014); 773: 285-307.
Rodriguez-Bravo V, Pippa R, Song WM, Carceles-Cordon M, Dominguez-Andres A, et al. Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import. Cell, (2018); 174(5):
-1215.
Franks TM, McCloskey A, Shokirev MN, Benner C, Rathore A, et al. Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. Genes & Development, (2017); 31(22): 2222-2234.
Agudo D, Gómez-Esquer F, Martínez-Arribas F, Núñez-Villar MJ, Pollán M, et al. Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer. International Journal of Cancer, (2004); 109(5): 717-20.
Bersini S, Lytle NK, Schulte R, Huang L, Wahl GM, et al. Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling. Life Sci Alliance, (2020); 3(1): e201900623.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discovery, (2012); 2(5): 401-4.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science Signaling, (2013); 6(269): pl1.
Khan AU, Qu R, Ouyang J, Dai J. Role of Nucleoporins and Transport Receptors in Cell Differentiation. Frontiers in Physiology, (2020); 11: 239.
Goldstein AL, Snay CA, Heath CV, Cole CN. Pleiotropic nuclear defects associated with a conditional allele of the novel nucleoporin Rat9p/Nup85p. Molecular Biology of the Cell, (1996); 7(6): 917-34.
Vasu S, Shah S, Orjalo A, Park M, Fischer WH, et al. Novel vertebrate nucleoporins Nup133 and Nup160 play a role in mRNA export. Journal of Cell Biology, (2001); 155(3): 339-54.
Boehmer T, Enninga J, Dales S, Blobel G, Zhong H. Depletion of a single nucleoporin, Nup107, prevents the assembly of a subset of nucleoporins into the nuclear pore complex. Proceedings of the National Academy of Sciences of the United States of America, (2003); 100(3): 981-5.
Moroianu J, Hijikata M, Blobel G, Radu A. Mammalian karyopherin alpha 1 beta and alpha 2 beta heterodimers: alpha 1 or alpha 2 subunit binds nuclear localization signal and beta subunit interacts with peptide repeat-containing nucleoporins. Proceedings of the National Academy of Sciences of the United States of America, (1995); 92(14): 6532-6.
Powers MA, Forbes DJ, Dahlberg JE, Lund E. The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways. Journal of Cell Biology, (1997); 136(2): 241-50.
Stagg SM, LaPointe P, Razvi A, Gürkan C, Potter CS, et al. Structural basis for cargo regulation of COPII coat assembly. Cell, (2008); 134(3): 474-84.
Loïodice I, Alves A, Rabut G, Van Overbeek M, Ellenberg J, et al. The entire Nup107-160 complex, including three new members, is targeted as one entity to kinetochores in mitosis. Molecular Biology of the Cell, (2004);
(7): 3333-44.
Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ. Proteomic analysis of the mammalian nuclear pore complex. Cell Biology Journal, (2002); 158(5): 915-27.
Rasala BA, Orjalo AV, Shen Z, Briggs S, Forbes DJ. ELYS is a dual nucleoporin/kinetochore protein required for nuclear pore assembly and proper cell division. Proceedings of the National Academy of Sciences of the United States of America, (2006); 103(47): 17801-6.
Van Laer L, Van Camp G, van Zuijlen D, Green ED, Verstreken M, et al. Refined mapping of a gene for autosomal dominant progressive sensorineural hearing loss (DFNA5) to a 2-cM region, and exclusion of a candidate gene that is expressed in the cochlea. European Journal of Human Genetics, (1997); 5(6): 397-405.
Beddow AL, Richards SA, Orem NR, Macara IG. The Ran/TC4 GTPase-binding domain: identification by expression cloning and characterization of a conserved sequence motif. Proceedings of the National Academy of Sciences of the United States of America, (1995); 92(8): 3328-32.
Kraemer D, Wozniak RW, Blobel G, Radu A. The human CAN protein, a putative oncogene product associated with myeloid leukemogenesis, is a nuclear pore complex protein that faces the cytoplasm. Proceedings of the National Academy of Sciences of the United States of America, (1994); 91(4): 1519-23.
Fornerod M, van Deursen J, van Baal S, Reynolds A, Davis D, Murti KG, Fransen J, Grosveld G. The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88. The EMBO Journal, (1997); 16(4): 807-16.
Tullio-Pelet A, Salomon R, Hadj-Rabia S, Mugnier C, de Laet MH, et al. Mutant WD-repeat protein in triple-A syndrome. Nature Genetics, (2000); 26(3): 332-5.
Watkins JL, Murphy R, Emtage JL, Wente SR. The human homologue of Saccharomyces cerevisiae Gle1p is required for poly(A)+ RNA export. Proceedings of the National Academy of Sciences of the United States of
America, (1998); 95(12): 6779-84.
Carmo-Fonseca M, Kern H, Hurt EC. Human nucleoporin p62 and the essential yeast nuclear pore protein NSP1 show sequence homology and a similar domain organization. European Journal of Cell Biology, (1991); 55(1): 17-30.
Strausberg RL, Feingold EA, Grouse LH, Derge JG et al. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United
States of America (2002); 99(26): 16899-903.
Bharathi A, Ghosh A, Whalen WA, Yoon JH, Pu R, et al. The human RAE1 gene is a functional homologue of Schizosaccharomyces pombe rae1 gene involved in nuclear export of Poly(A)+ RNA. Gene, (1997); 198(1-2): 251-8.
Grandi P, Dang T, Pané N, Shevchenko A, Mann M, et al. Nup93, a vertebrate homologue of yeast Nic96p, forms a complex with a novel 205-kDa protein and is required for correct nuclear pore assembly. Molecular Biology of the Cell, (1997); 8(10): 2017-38.
Miller BR, Powers M, Park M, Fischer W, Forbes DJ. Identification of a new vertebrate nucleoporin, Nup188, with the use of a novel organelle trap assay. Molecular Biology of the Cell, (2000); 11(10): 3381-96.
Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, et al. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Research, (1996); 3(5): 321-9, 341-54.
Handa N, Kukimoto-Niino M, Akasaka R, Kishishita S, Murayama K, et al. The crystal structure of mouse Nup35 reveals atypical RNP motifs and novel homodimerization of the RRM domain. Journal of Molecular Biology, (2006); 363(1): 114-24.
Zhang X, Yang H, Corydon MJ, Zhang X, Pedersen S, et al. Localization of a human nucleoporin 155 gene (NUP155) to the 5p13 region and cloning of its cDNA. Genomics, (1999); 57(1): 144-51.
Krull S, Thyberg J, Björkroth B, Rackwitz HR, Cordes VC. Nucleoporins as components of the nuclear pore complex core structure and Tpr as the architectural element of the nuclear basket. Molecular Biology of the Cell, (2004); 15(9): 4261-77.
McMorrow I, Bastos R, Horton H, Burke B. Sequence analysis of a cDNA encoding a human nuclear pore complex protein, hnup153. Biochimica et Biophysica Acta, (1994); 1217(2): 219-23.
Trichet V, Shkolny D, Dunham I, Beare D, McDermid HE. Mapping and complex expression pattern of the human NPAP60L nucleoporin gene. Cytogenetic and Genome Research, (1999); 85(3-4):221-6.
Schirmer EC, Florens L, Guan T, Yates JR 3rd, Gerace L. Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science, (2003); 301(5638): 1380-2.
Greber UF, Senior A, Gerace L. A major glycoprotein of the nuclear pore complex is a membrane-spanning polypeptide with a large lumenal domain and a small cytoplasmic tail. The EMBO Journal, (1990); 9(5): 1495-502.
Gusev FE, Reshetov DA, Mitchell AC, Andreeva TV, Dincer A, et al. Epigenetic-genetic chromatin footprinting identifies novel and subject-specific genes active in prefrontal cortex neurons. The FASEB Journal, (2019); 33(7): 8161-8173.
Hallberg E, Wozniak RW, Blobel G. An integral membrane protein of the pore membrane domain of the nuclear envelope contains a nucleoporin-like region. Journal of Cell Biology, (1993); 122(3): 513-21.
Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, et al. The DNA sequence and analysis of human chromosome 6. Nature, (2003); 425(6960): 805-11.
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature Genetics, (2004); 36(1): 40-5.
Funakoshi T, Maeshima K, Yahata K, Sugano S, Imamoto F, et al. Two distinct human POM121 genes: requirement for the formation of nuclear pore complexes. FEBS Letters, (2007); 581(25): 4910-6.
Ishikawa K, Nagase T, Nakajima D, Seki N, Ohira M, et al. Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro. DNA Research, (1997); 4(5): 307-13.
Hu T, Guan T, Gerace L. Molecular and functional characterization of the p62 complex, an assembly of nuclear pore complex glycoproteins. Journal of Cell Biology, (1996); 134(3): 589-601.
Schmitt C, von Kobbe C, Bachi A, Panté N, Rodrigues JP, et al. Dbp5, a DEAD-box protein required for mRNA export, is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN/Nup159p. The EMBO Journal, (1999); 18(15): 4332-47.
Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, et al. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Research, (2011); 39(Database issue): D561-8.
Goldman MJ, Craft B, Hastie M, Repečka K, McDade F, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nature Biotechnology, (2020); 38(6): 675-678.
GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nature Genetics, (2013); 45(6): 580-5.
Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Research and Treatment, (2010); 123(3): 725-31.
Mehmood R, Jibiki K, Shibazaki N, Yasuhara N. Molecular profiling of nucleocytoplasmic transport factor genes in breast cancer. Heliyon, (2021); 7(1): e06039.
Holzer G, Antonin W. Breaking the Y. PLOS Genetics, (2019); 15(5): e1008109.
Souquet B, Freed E, Berto A, Andric V, Audugé N, et al. Nup133 Is Required for Proper Nuclear Pore Basket Assembly and Dynamics in Embryonic Stem Cells. Cell Reports, (2018); 23(8): 2443-2454.
Jevtić P, Schibler AC, Wesley CC, Pegoraro G, Misteli T, et al. The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity. EMBO reports, (2019); 20(6): e47283.
Stanley GJ, Fassati A, Hoogenboom BW. Biomechanics of the transport barrier in the nuclear pore complex. Seminars in Cell & Developmental Biology, (2017); 68: 42-51.
Tian C, Zhou S, Yi C. High NUP43 expression might independently predict poor overall survival in luminal A and in HER2+ breast cancer. Future Oncology, (2018); 14(15): 1431-1442.
Mullan PB, Bingham V, Haddock P, Irwin GW, Kay E, et al. NUP98 – a novel predictor of response to anthracycline-based chemotherapy in triple negative breast cancer. BMC Cancer, (2019); 19(1): 236.
Michmerhuizen NL, Klco JM, Mullighan CG. Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies. Blood, (2020); 136(20): 2275-2289.
Aramburu IV, Lemke EA. Floppy but not sloppy: Interaction mechanism of FG-nucleoporins and nuclear transport receptors. Seminars in Cell & Developmental Biology, (2017); 68: 34-41.
Nakano H, Wang W, Hashizume C, Funasaka T, Sato H, et al. Unexpected role of nucleoporins in coordination of cell cycle pro-gression. Cell Cycle, (2011); 10(3): 425-33.
Holzer K, Ori A, Cooke A, Dauch D, Drucker E, et al. Nucleoporin Nup155 is part of the p53 network in liver cancer. Nature Communications, (2019); 10(1): 2147.
Kehat I, Accornero F, Aronow BJ, Molkentin JD. Modulation of chromatin position and gene expression by HDAC4 interaction with nucleoporins. Cell Biology Journal, (2011); 193(1): 21-9.
Preston CC, Storm EC, Burdine RD, Bradley TA, Uttecht AD, et al. Nucleoporin insufficiency disrupts a pluripotent regulatory circuit in a pro-arrhythmogenic stem cell line. Scientific Reports, (2019); 9(1): 12691.
Enninga J, Levay A, Fontoura BM. Sec13 shuttles between the nucleus and the cytoplasm and stably interacts with Nup96 at the nuclear pore complex. Molecular and Cellular Biology, (2003); 23(20): 7271-84.
Lim KS, Wong RW. Targeting Nucleoporin POM121-Importin β Axis in Prostate Cancer. Cell Chemical Biology, (2018); 25(9): 1056-1058.
Wang H, Lin Y, Jin J, Shen H, Dai C. Nuclear Pore Complex 62 Promotes Metastasis of Gastric Cancer by Regulating Wnt/β-Catenin and TGF-β Signaling Pathways. Journal of Environmental Pathology, Toxicology and Oncology, (2021); 40(2): 81-87.
Ribbeck K, Görlich D. The permeability barrier of nuclear pore complexes appears to operate via hydrophobic exclusion. The EMBO Journal, (2002); 21(11): 2664-71.
Liashkovich I, Pasrednik D, Prystopiuk V, Rosso G, Oberleithner H, et al. Clathrin inhibitor Pitstop-2 disrupts the nuclear pore complex permeability barrier. Scientific Reports, (2015); 5: 9994.
DOI: http://dx.doi.org/10.62940/als.v9i1.1336
Refbacks
- There are currently no refbacks.