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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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Figure 1: Identification of USP15 as a regulator of the TGF-β signaling pathway.
Figure 2: USP15 forms a complex with SMAD7 and SMURF2.
Figure 3: USP15 regulates TβR-I stability and counteracts SMURF2 activity.
Figure 4: USP15 regulates the TGF-β signaling pathway in human GBM.
Figure 5: USP15 is targeted for gene amplification.
Figure 6: Knockdown of USP15 inhibits TGF-β activity and the oncogenic potential of patient-derived GBM neurospheres.

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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.

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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.

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Correspondence to Joan Seoane.

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The authors declare no competing financial interests.

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Eichhorn, P., Rodón, L., Gonzàlez-Juncà, A. et al. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med 18, 429–435 (2012). https://doi.org/10.1038/nm.2619

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