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

• Published in: Nature medicine Vol. 18; no. 3; pp. 429 - 435
• Main Authors: Eichhorn, Pieter J A, Rodón, Laura, Gonzàlez-Juncà, Alba, Dirac, Annette, Gili, Magüi, Martínez-Sáez, Elena, Aura, Claudia, Barba, Ignasi, Peg, Vicente, Prat, Aleix, Cuartas, Isabel, Jimenez, Jose, García-Dorado, David, Sahuquillo, Juan, Bernards, Réné, Baselga, José, Seoane, Joan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2012; Nature Publishing Group
• Subjects: 631/250/516; 631/337/505; 631/45/474/2289; 692/699/67; Animals; Biomedical and Life Sciences; Biomedicine; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Cancer Research; Care and treatment; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cellular signal transduction; Disease Models, Animal; Endopeptidases - genetics; Endopeptidases - metabolism; Gene Expression Regulation, Neoplastic; Genetic aspects; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma multiforme; HEK293 Cells; Humans; Infectious Diseases; Magnetic Resonance Imaging; Metabolic Diseases; Mice; Molecular Medicine; Neurosciences; Phosphorylation; Physiological aspects; Prognosis; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Risk factors; RNA Interference; Signal Transduction; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad7 Protein - metabolism; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming growth factors; Ubiquitin; Ubiquitin-Protein Ligases - metabolism; Ubiquitin-Specific Proteases; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2619

TGF-β signaling is commonly aberrantly activated in gliomas and other tumors and can exert a pro-oncogenic function. The authors identify a new mechanism for upregulation of TGF-β signaling in cancer. The deubiquitinase USP15 is shown to be able to bind the TGF-β receptor complex, counteract its degradation and potentiate its stimulation of downstream mediators. USP15 is amplified in human glioblastoma and could represent a therapeutic target, as its downregulation impairs the growth of glioblastoma cells in vivo . 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.