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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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.
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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