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USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma

Nature Medicine volume 18, pages 429435 (2012) | Download Citation

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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Acknowledgements

We thank A. Sáez-Borderías and A. Arias for technical support. We also thank the Medical Oncology department, the Neurosurgery department and the Pathology department of the Vall d'Hebron Hospital for support. E.M.S. is supported by the Instituto Carlos III (CM09/143). I.B. and D.G.-D. were supported by the Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (RECAVA, ISCIII). This work was supported by the European Research Council grant (ERC 205819), Instituto Carlos III grant FIS (PI070648), Ministry of Science and Innovation grant Consolider Ingenio 2010 program (CSD2009-00080) and the Asociación Española Contra el Cáncer (AECC) grant.

Author information

Affiliations

  1. Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.

    • Pieter J A Eichhorn
    • , Laura Rodón
    • , Alba Gonzàlez-Juncà
    • , Magüi Gili
    • , Claudia Aura
    • , Aleix Prat
    • , Isabel Cuartas
    • , Jose Jimenez
    • , José Baselga
    •  & Joan Seoane
  2. Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

    • Annette Dirac
    •  & Réné Bernards
  3. Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain.

    • Elena Martínez-Sáez
    • , Ignasi Barba
    • , Vicente Peg
    • , David García-Dorado
    •  & Juan Sahuquillo
  4. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Aleix Prat
  5. Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

    • José Baselga
    •  & Joan Seoane
  6. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.

    • José Baselga
  7. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

    • Joan Seoane

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Contributions

P.J.A.E., L.R. and A.G.-J. performed all the experiments. A.D. and R.B. generated the DUB shRNA library. M.G. technically assisted in performing the in vitro experiments. E.M.-S., C.A., V.P. and J.J. performed the pathology analysis of the specimens. A.P. performed the bioinformatic analysis. I.B. and D.G.-D. performed the MRI analysis. I.C. performed the intracranial injections and technically assisted in the in vivo experiments. J. Sahuquillo was in charge of the human neurosurgical procedures. J.B. was in charge of the clinical analysis. J. Seoane designed and supervised the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joan Seoane.

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DOI

https://doi.org/10.1038/nm.2619

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