USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma
Abstract
In advanced cancer, including glioblastoma, the transforming growth factor β (TGF-β) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-β signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-β receptor (TβR-I), leading to an enhanced TGF-β signal. High expression of USP15 correlates with high TGF-β activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-β signaling. Our results show that USP15 regulates the TGF-β pathway and is a key factor in glioblastoma pathogenesis.
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USP15 shows dual effects in tumorigenesis; USP15 copy number is increased in glioblastoma, breast cancer, and ovarian cancer, but decreased in pancreatic cancer.
“Due to the conflicting functions of substrates, USP15 shows dual effects in tumorigenesis. For instance, USP15 copy number is increased in glioblastoma, breast cancer, and ovarian cancer, but decreased in pancreatic cancer40,52,55–58.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [40]
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“For instance, USP15 copy number is increased in glioblastoma, breast cancer, and ovarian cancer, but decreased in pancreatic cancer 40,52,55 – 58 .”
BackgroundChoi, M., Chaudhari, H. N., Ji, Y. R., Ryoo, Z. Y., Kim, S. W., & Yun, J. W. (2015) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-015-2468-1 · Cited by 7 · see citing works
- Authors
- Eichhorn, P. J. A., Rodón, L., Gonzàlez-Juncà, A., Dirac, A., Gili, M., Martínez-Sáez, E., Aura, C., Barba, I., Peg, V., Prat, A., Cuartas, I., Jimenez, J., García-Dorado, D., Sahuquillo, J., Bernards, R., Baselga, J., & Seoane, J.
- Affiliations
- Vall d'Hebron Hospital Universitari (ES)
- The Netherlands Cancer Institute (NL)
- Vall d'Hebron Institut de Recerca (ES)
- University of North Carolina at Chapel Hill (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Seoane, Joan
- ORCID
- Venue
- Nature Medicine
- Published
- 2012-02-19
- Volume
- 18
- Issue
- 3
- Pages
- 429-435
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2128345996
- Cited by
- 409
- References
- 0
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 31 · 2023: 23 · 2022: 31 · 2021: 34 · 2020: 36 · 2019: 26 · 2018: 29 · 2017: 30 · 2016: 33 · 2015: 22 · 2014: 30 · 2013: 30 · 2012: 14
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- USP15, TGF-beta signaling, TGF-beta type I receptor, glioblastoma, protein stabilization, deubiquitination, Smurf2, Smad7, carcinogenesis, gene amplification, glioma stem cells, therapeutic target
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Animals, Brain Neoplasms, Cell Transformation, Neoplastic, Disease Models, Animal, Glioblastoma, Humans, Magnetic Resonance Imaging, Endopeptidases, Phosphorylation, Prognosis, Signal Transduction, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Ubiquitin, RNA Interference, Ubiquitin-Protein Ligases, Cell Line, Tumor, Mice, Smad2 Protein, Smad7 Protein, HEK293 Cells, Ubiquitin-Specific Proteases
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