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

Date

2019-09

Author

Kagiali, Zeynep Cansu Üretmen
Sanal, Erdem
Karayel, Özge
Polat, Ayşe Nur
Saatçi, Özge
Ersan, Pelin Gülizar
Trappe, Kathrin
Renard, Bernhard Y.
Önder, Tamer T.
Tunçbağ, Nurcan
Şahin, Özgür
Özlü, Nurhan

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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 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

Subject Keywords

Tumor-Suppressor, Drug-Resistance, Stem-Cells, Protein, Enrichment, Emt, Mechanisms, Inhibition, Resource, Platform

URI

https://hdl.handle.net/11511/28657
https://dx.doi.org/10.1074/mcp.RA119.001446

Collections

Graduate School of Informatics, Article