Systems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast cancer

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buir.contributor.authorErsan, Pelin Gülizar
buir.contributor.authorŞahin, Özgür
dc.citation.epage1771en_US
dc.citation.issueNumber9en_US
dc.citation.spage1756en_US
dc.citation.volumeNumber18en_US
dc.contributor.authorÜretmen-Kagıalı, Z. C.en_US
dc.contributor.authorSanal, E.en_US
dc.contributor.authorKarayel, Ö.en_US
dc.contributor.authorPolat, A. N.en_US
dc.contributor.authorSaatci, Ö.en_US
dc.contributor.authorErsan, Pelin Gülizaren_US
dc.contributor.authorTrappe, K.en_US
dc.contributor.authorRenard, B. Y.en_US
dc.contributor.authorÖnder, T. T.en_US
dc.contributor.authorTunçbağ, N.en_US
dc.contributor.authorŞahin, Özgüren_US
dc.contributor.authorÖzlü, N.en_US
dc.date.accessioned2020-02-17T11:28:16Z
dc.date.available2020-02-17T11:28:16Z
dc.date.issued2019
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractEpithelial-mesenchymal transition (EMT) is driven by complex signaling events that induce dramatic biochemical and morphological changes whereby epithelial cells are converted into cancer cells. However, the underlying molecular mechanisms remain elusive. Here, we used mass spectrometry based quantitative proteomics approach to systematically analyze the post-translational biochemical changes that drive differentiation of human mammary epithelial (HMLE) cells into mesenchymal. We identified 314 proteins out of more than 6,000 unique proteins and 871 phosphopeptides out of more than 7,000 unique phosphopeptides as differentially regulated. We found that phosphoproteome is more unstable and prone to changes during EMT compared with the proteome and multiple alterations at proteome level are not thoroughly represented by transcriptional data highlighting the necessity of proteome level analysis. We discovered cell state specific signaling pathways, such as Hippo, sphingolipid signaling, and unfolded protein response (UPR) by modeling the networks of regulated proteins and potential kinase-substrate groups. We identified two novel factors for EMT whose expression increased on EMT induction: DnaJ heat shock protein family (Hsp40) member B4 (DNAJB4) and cluster of differentiation 81 (CD81). Suppression of DNAJB4 or CD81 in mesenchymal breast cancer cells resulted in decreased cell migration in vitro and led to reduced primary tumor growth, extravasation, and lung metastasis in vivo. Overall, we performed the global proteomic and phosphoproteomic analyses of EMT, identified and validated new mRNA and/or protein level modulators of EMT. This work also provides a unique platform and resource for future studies focusing on metastasis and drug resistance.en_US
dc.identifier.doi10.1074/mcp.RA119.001446en_US
dc.identifier.issn1535-9476
dc.identifier.urihttp://hdl.handle.net/11693/53393
dc.language.isoEnglishen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.relation.isversionofhttps://dx.doi.org/10.1074/mcp.RA119.001446en_US
dc.source.titleMolecular and Cellular Proteomicsen_US
dc.subjectPhosphoproteomeen_US
dc.subjectMetastasisen_US
dc.subjectBreast canceren_US
dc.subjectKinasesen_US
dc.subjectQuantificationen_US
dc.subjectMouse modelsen_US
dc.subjectCD81en_US
dc.subjectDNAJB4en_US
dc.subjectEMTen_US
dc.titleSystems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast canceren_US
dc.typeArticleen_US

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