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Molecular & Cellular Proteomics

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

View ORCID ProfileZeynep Cansu Uretmen Kagiali, Erdem Sanal, Özge Karayel, Ayse Nur Polat, Özge Saatci, Pelin Gülizar Ersan, Kathrin Trappe, Bernhard Y. Renard, View ORCID ProfileTamer T. Önder, Nurcan Tuncbag, Özgür Şahin and View ORCID ProfileNurhan Ozlu  Correspondence email
Molecular & Cellular Proteomics June 20, 2019, mcp.RA119.001446; https://doi.org/10.1074/mcp.RA119.001446
Zeynep Cansu Uretmen Kagiali
Koç University, Turkey
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  • ORCID record for Zeynep Cansu Uretmen Kagiali
Erdem Sanal
Koç University, Turkey
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Özge Karayel
Koç University, Turkey
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Ayse Nur Polat
Koç University, Turkey
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Özge Saatci
University of South Carolina, United States
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Pelin Gülizar Ersan
Bilkent University, Turkey
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Kathrin Trappe
Robert Koch Institute, Germany
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Bernhard Y. Renard
MF1 Bioinformatics Unit, Robert Koch Institute, Germany
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Tamer T. Önder
Koç University, Turkey
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  • ORCID record for Tamer T. Önder
Nurcan Tuncbag
Middle East Technical University, Turkey
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Özgür Şahin
University of South Carolina, United StatesBilkent University, Turkey
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Nurhan Ozlu
Koç University, Turkey
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  • ORCID record for Nurhan Ozlu
  • For correspondence: nozlu@ku.edu.tr
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Abstract

Epithelial-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 to 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 upon 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.

  • Twist
  • DNAJB4
  • CD81
  • EMT
  • ‘omic’ data integration
  • Breast cancer
  • Cancer biomarker(s)
  • Kinases*
  • Metastasis
  • Mouse models
  • Networks*
  • Phosphoproteome
  • Quantification

Footnotes

  • Author contributions: Z.C.U.K., x.K., A.N.P., P.G.E., and x.x. performed research; Z.C.U.K., E.S., and N.O. wrote the paper; E.S., x.S., K.T., B.Y.R., N.T., and N.O. analyzed data; T.T.x. and x.x. contributed new reagents/analytic tools; N.T. and N.O. designed research.

  • Received March 15, 2019.
  • Revision received May 21, 2019.
  • Accepted June 20, 2019.
  • Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
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Systems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast cancer
Zeynep Cansu Uretmen Kagiali, Erdem Sanal, Özge Karayel, Ayse Nur Polat, Özge Saatci, Pelin Gülizar Ersan, Kathrin Trappe, Bernhard Y. Renard, Tamer T. Önder, Nurcan Tuncbag, Özgür Şahin, Nurhan Ozlu
Molecular & Cellular Proteomics June 20, 2019, mcp.RA119.001446; DOI: 10.1074/mcp.RA119.001446

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Systems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast cancer
Zeynep Cansu Uretmen Kagiali, Erdem Sanal, Özge Karayel, Ayse Nur Polat, Özge Saatci, Pelin Gülizar Ersan, Kathrin Trappe, Bernhard Y. Renard, Tamer T. Önder, Nurcan Tuncbag, Özgür Şahin, Nurhan Ozlu
Molecular & Cellular Proteomics June 20, 2019, mcp.RA119.001446; DOI: 10.1074/mcp.RA119.001446
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