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Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1

BACKGROUND: The cell-surface heparan sulfate proteoglycan syndecan-1 is important for tumor cell proliferation, migration, and cell cycle regulation in a broad spectrum of malignancies. Syndecan-1, however, also translocates to the cell nucleus, where it might regulate various molecular functions. R...

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Autores principales: Szatmári, Tünde, Mundt, Filip, Kumar-Singh, Ashish, Möbus, Lena, Ötvös, Rita, Hjerpe, Anders, Dobra, Katalin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721467/
https://www.ncbi.nlm.nih.gov/pubmed/29216821
http://dx.doi.org/10.1186/s12860-017-0150-z
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author Szatmári, Tünde
Mundt, Filip
Kumar-Singh, Ashish
Möbus, Lena
Ötvös, Rita
Hjerpe, Anders
Dobra, Katalin
author_facet Szatmári, Tünde
Mundt, Filip
Kumar-Singh, Ashish
Möbus, Lena
Ötvös, Rita
Hjerpe, Anders
Dobra, Katalin
author_sort Szatmári, Tünde
collection PubMed
description BACKGROUND: The cell-surface heparan sulfate proteoglycan syndecan-1 is important for tumor cell proliferation, migration, and cell cycle regulation in a broad spectrum of malignancies. Syndecan-1, however, also translocates to the cell nucleus, where it might regulate various molecular functions. RESULTS: We used a fibrosarcoma model to dissect the functions of syndecan-1 related to the nucleus and separate them from functions related to the cell-surface. Nuclear translocation of syndecan-1 hampered the proliferation of fibrosarcoma cells compared to the mutant lacking nuclear localization signal. The growth inhibitory effect of nuclear syndecan-1 was accompanied by significant accumulation of cells in the G0/G1 phase, which indicated a possible G1/S phase arrest. We implemented multiple, unsupervised global transcriptome and proteome profiling approaches and combined them with functional assays to disclose the molecular mechanisms that governed nuclear translocation and its related functions. We identified genes and pathways related to the nuclear compartment with network enrichment analysis of the transcriptome and proteome. The TGF-β pathway was activated by nuclear syndecan-1, and three genes were significantly altered with the deletion of nuclear localization signal: EGR-1 (early growth response 1), NEK11 (never-in-mitosis gene a-related kinase 11), and DOCK8 (dedicator of cytokinesis 8). These candidate genes were coupled to growth and cell-cycle regulation. Nuclear translocation of syndecan-1 influenced the activity of several other transcription factors, including E2F, NFκβ, and OCT-1. The transcripts and proteins affected by syndecan-1 showed a striking overlap in their corresponding biological processes. These processes were dominated by protein phosphorylation and post-translation modifications, indicative of alterations in intracellular signaling. In addition, we identified molecules involved in the known functions of syndecan-1, including extracellular matrix organization and transmembrane transport. CONCLUSION: Collectively, abrogation of nuclear translocation of syndecan-1 resulted in a set of changes clustering in distinct patterns, which highlighted the functional importance of nuclear syndecan-1 in hampering cell proliferation and the cell cycle. This study emphasizes the importance of the localization of syndecan-1 when considering its effects on tumor cell fate. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12860-017-0150-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-57214672017-12-11 Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1 Szatmári, Tünde Mundt, Filip Kumar-Singh, Ashish Möbus, Lena Ötvös, Rita Hjerpe, Anders Dobra, Katalin BMC Cell Biol Research Article BACKGROUND: The cell-surface heparan sulfate proteoglycan syndecan-1 is important for tumor cell proliferation, migration, and cell cycle regulation in a broad spectrum of malignancies. Syndecan-1, however, also translocates to the cell nucleus, where it might regulate various molecular functions. RESULTS: We used a fibrosarcoma model to dissect the functions of syndecan-1 related to the nucleus and separate them from functions related to the cell-surface. Nuclear translocation of syndecan-1 hampered the proliferation of fibrosarcoma cells compared to the mutant lacking nuclear localization signal. The growth inhibitory effect of nuclear syndecan-1 was accompanied by significant accumulation of cells in the G0/G1 phase, which indicated a possible G1/S phase arrest. We implemented multiple, unsupervised global transcriptome and proteome profiling approaches and combined them with functional assays to disclose the molecular mechanisms that governed nuclear translocation and its related functions. We identified genes and pathways related to the nuclear compartment with network enrichment analysis of the transcriptome and proteome. The TGF-β pathway was activated by nuclear syndecan-1, and three genes were significantly altered with the deletion of nuclear localization signal: EGR-1 (early growth response 1), NEK11 (never-in-mitosis gene a-related kinase 11), and DOCK8 (dedicator of cytokinesis 8). These candidate genes were coupled to growth and cell-cycle regulation. Nuclear translocation of syndecan-1 influenced the activity of several other transcription factors, including E2F, NFκβ, and OCT-1. The transcripts and proteins affected by syndecan-1 showed a striking overlap in their corresponding biological processes. These processes were dominated by protein phosphorylation and post-translation modifications, indicative of alterations in intracellular signaling. In addition, we identified molecules involved in the known functions of syndecan-1, including extracellular matrix organization and transmembrane transport. CONCLUSION: Collectively, abrogation of nuclear translocation of syndecan-1 resulted in a set of changes clustering in distinct patterns, which highlighted the functional importance of nuclear syndecan-1 in hampering cell proliferation and the cell cycle. This study emphasizes the importance of the localization of syndecan-1 when considering its effects on tumor cell fate. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12860-017-0150-z) contains supplementary material, which is available to authorized users. BioMed Central 2017-12-08 /pmc/articles/PMC5721467/ /pubmed/29216821 http://dx.doi.org/10.1186/s12860-017-0150-z Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Szatmári, Tünde
Mundt, Filip
Kumar-Singh, Ashish
Möbus, Lena
Ötvös, Rita
Hjerpe, Anders
Dobra, Katalin
Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1
title Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1
title_full Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1
title_fullStr Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1
title_full_unstemmed Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1
title_short Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1
title_sort molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721467/
https://www.ncbi.nlm.nih.gov/pubmed/29216821
http://dx.doi.org/10.1186/s12860-017-0150-z
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