PUBLICATION
Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis
- Authors
- Liu, S., González Prieto, R., Zhang, M., Geurink, P.P., Kooij, R., Iyengar, P.V., van Dinther, M., Bos, E., Zhang, X., Le Dévédec, S.E., van de Water, B., Koning, R.I., Zhu, H.J., Mesker, W.E., Vertegaal, A., Ovaa, H., Zhang, L., Martens, J.W.M., Ten Dijke, P.
- ID
- ZDB-PUB-191223-3
- Date
- 2019
- Source
- Clinical cancer research : an official journal of the American Association for Cancer Research 26(6): 1460-1473 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Biomarkers, Tumor/blood*
- Biomarkers, Tumor/genetics
- Cell Line, Tumor
- Cell Proliferation
- Deubiquitinating Enzymes/metabolism*
- Female
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Metastasis
- Oncogene Proteins/genetics
- Oncogene Proteins/metabolism*
- Signal Transduction
- Transforming Growth Factor beta/genetics
- Transforming Growth Factor beta/metabolism*
- Triple Negative Breast Neoplasms/enzymology
- Triple Negative Breast Neoplasms/genetics
- Triple Negative Breast Neoplasms/pathology*
- Ubiquitin Thiolesterase/genetics
- Ubiquitin Thiolesterase/metabolism*
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 31857432 Full text @ Clin. Cancer Res.
Citation
Liu, S., González Prieto, R., Zhang, M., Geurink, P.P., Kooij, R., Iyengar, P.V., van Dinther, M., Bos, E., Zhang, X., Le Dévédec, S.E., van de Water, B., Koning, R.I., Zhu, H.J., Mesker, W.E., Vertegaal, A., Ovaa, H., Zhang, L., Martens, J.W.M., Ten Dijke, P. (2019) Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research. 26(6):1460-1473.
Abstract
Purpose Therapies directed to specific molecular targets are still unmet for triple-negative breast cancer (TNBC) patients. Deubiquitinases (DUBs) are emerging drug targets. The identification of a 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 synthesised 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 TNBC patient sera, 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping