TGFβ-Activated USP27X Deubiquitinase Regulates Cell Migration and Chemoresistance via Stabilization of Snail1
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In cancer cells, epithelial-to-mesenchymal transition (EMT) is controlled by Snail1, a transcriptional factor also required for the activation of cancer-associated fibroblasts (CAF). Snail1 is short-lived in normal epithelial cells as a consequence of its coordinated and continuous ubiquitination by several F-box–specific E3 ligases, but its degradation is prevented in cancer cells and in activated fibroblasts. Here, we performed an siRNA screen and identified USP27X as a deubiquitinase that increases Snail1 stability. Expression of USP27X in breast and pancreatic cancer cell lines and tumors positively correlated with Snail1 expression levels. Accordingly, downregulation of USP27X decreased Snail1 protein in several tumor cell lines. USP27X depletion impaired Snail1-dependent cell migration and invasion and metastasis formation and increased cellular sensitivity to cisplatin. USP27X was upregulated by TGFβ during EMT and was required for TGFβ-induced expression of Snail1 and other mesenchymal markers in epithelial cells and CAF. In agreement with this, depletion of USP27X prevented TGFβ-induced EMT and fibroblast activation. Collectively, these results indicate that USP27X is an essential protein controlling Snail1 expression and function and may serve as a target for inhibition of Snail1-dependent tumoral invasion and chemoresistance. Significance: These findings show that inhibition of USP27X destabilizes Snail1 to impair EMT and renders tumor cells sensitive to chemotherapy, thus opening new strategies for the inhibition of Snail1 expression and its protumoral actions.
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Knock-down of certain deubiquitinases significantly decreased Snail1 levels, suggesting that DUBs promote Snail1 stabilization and are required for its effects on EMT and cancer progression.
“In a previous siRNA screening, we found that the knock-down of certain deubiquitinases (DUBs) significantly decreased Snail1 levels, suggesting that DUBs promote Snail1 stabilization and are required for its effects on EMT and cancer progression20.”
From Bioactivity descriptors for uncharacterized chemical compounds (2021) · cites this paper as [20]
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- Authors
- Lambies, G., Miceli, M., Martínez-Guillamon, C., Olivera-Salguero, R., Peña, R., Frías, C.-P., Calderón, I., Atanassov, B. S., Dent, S. Y. R., Arribas, J., García de Herreros, A., & Díaz, V. M.
- Affiliations
- Universitat Pompeu Fabra (ES)
- Hospital del Mar Research Institute (ES)
- 1Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Unidad Asociada CSIC, Barcelona, Spain.
- Roswell Park Comprehensive Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- 5Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) CIBERONC, Barcelona, Spain.
- ORCID
- Venue
- Cancer Research
- Published
- 2019-01-01
- Volume
- 79
- Issue
- 1
- Pages
- 33-46
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC9386731
- OpenAlex
- W2897751391
- Cited by
- 99
- References
- 49
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 21 · 2023: 11 · 2022: 12 · 2021: 18 · 2020: 13 · 2019: 10 · 2018: 1
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- MINECO FEDER (SAF2013-48849-C2-1-R, SAF2016-76461-R, SAF2013-48849-C2-2-R)
- Instituto de Salud Carlos III (PIE15/00008, PI16/00253)
- NCI (P30CA016056)
- Breast Cancer Research Foundation (BCRF-17-008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- SNAI1, TGF-beta, epithelial-mesenchymal transition, deubiquitinase, protein stability, cancer-associated fibroblasts, cell migration, chemoresistance, cisplatin sensitivity, metastasis, breast cancer, pancreatic cancer, E3 ubiquitin ligase
- MeSH terms
- Snail Family Transcription Factors, Cancer-Associated Fibroblasts, Animals, Breast Neoplasms, Cell Movement, Female, Humans, Neoplasm Invasiveness, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Ubiquitin, RNA, Small Interfering, Mice, Protein Stability, Epithelial-Mesenchymal Transition, Ubiquitin-Specific Proteases
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