2. Academic Validation
  3. Deubiquitinase Activity Profiling Identifies UCHL1 as a Candidate Oncoprotein That Promotes TGFβ-Induced Breast Cancer Metastasis

Deubiquitinase Activity Profiling Identifies UCHL1 as a Candidate Oncoprotein That Promotes TGFβ-Induced Breast Cancer Metastasis

  • Clin Cancer Res. 2020 Mar 15;26(6):1460-1473. doi: 10.1158/1078-0432.CCR-19-1373.
Sijia Liu 1 2,  Román González-Prieto 1,  Mengdi Zhang 3,  Paul P Geurink 1 2,  Raymond Kooij 1 2,  Prasanna Vasudevan Iyengar 1 2,  Maarten van Dinther 1 2,  Erik Bos 1,  Xiaobing Zhang 4,  Sylvia E Le Dévédec 4,  Bob van de Water 4,  Roman I Koning 1,  Hong-Jian Zhu 5,  Wilma E Mesker 6,  Alfred C O Vertegaal 1,  Huib Ovaa 1 2,  Long Zhang 3,  John W M Martens 7,  Peter Ten Dijke 8 2
Affiliations

Affiliations

  • 1 Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
  • 2 Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.
  • 3 Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China.
  • 4 Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden, the Netherlands.
  • 5 Department of Surgery, The University of Melbourne, Melbourne, Australia.
  • 6 Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
  • 7 Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
  • 8 Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. [email protected].
PMID: 31857432 DOI: 10.1158/1078-0432.CCR-19-1373
Abstract

Purpose: Therapies directed to specific molecular targets are still unmet for patients with triple-negative breast Cancer (TNBC). Deubiquitinases (DUB) are emerging drug targets. The identification of highly active DUBs in TNBC may lead to novel therapies.

Experimental design: Using DUB activity probes, we profiled global DUB activities in 52 breast Cancer cell lines and 52 patients' tumor tissues. To validate our findings in vivo, we employed both zebrafish and murine breast Cancer xenograft models. Cellular and molecular mechanisms were elucidated using in vivo and in vitro biochemical methods. A specific inhibitor was synthesized, and its biochemical and biological functions were assessed in a range of assays. Finally, we used patient sera samples to investigate clinical correlations.

Results: Two DUB activity profiling approaches identified UCHL1 as being highly active in TNBC cell lines and aggressive tumors. Functionally, UCHL1 promoted metastasis in zebrafish and murine breast Cancer xenograft models. Mechanistically, UCHL1 facilitates TGFβ signaling-induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination. We found that these responses are potently suppressed by the specific UCHL1 Inhibitor, 6RK73. Furthermore, UCHL1 levels were significantly increased in sera of patients with TNBC, and highly enriched in sera exosomes as well as TNBC cell-conditioned media. UCHL1-enriched exosomes stimulated breast Cancer migration and extravasation, suggesting that UCHL1 may act in a paracrine manner to promote tumor progression.

Conclusions: Our DUB activity profiling identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast Cancer metastasis and may provide a potential target for TNBC treatment.

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