Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition
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Asoka Banno1,*, Daniel A. Garcia1,*, Eric D. van Baarsel1, Patrick J. Metz1, Kathleen Fisch2, Christella E. Widjaja1, Stephanie H. Kim1, Justine Lopez1, Aaron N. Chang2, Paul P. Geurink4, Bogdan I. Florea3, Hermen S. Overkleeft3, Huib Ovaa4, Jack D. Bui5, Jing Yang6,7,8 and John T. Chang1
1 Department of Medicine, University of California San Diego, La Jolla, CA, USA
2 Center for Computational Biology and Bioinformatics, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
3 Division of Chemical Biology, Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Leiden, The Netherlands
4 Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
5 Department of Pathology, University of California San Diego, La Jolla, CA, USA
6 Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
7 Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
8 Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
* These authors have contributed equally to this article
John T. Chang, email:
Keywords: EMT, proteasome, TGF-beta, cancer stem cells
Received: October 10, 2015 Accepted: January 24, 2016 Published: February 22, 2016
The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy.
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