title: 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.
authors.affiliation: Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Pieter J A
authors.initials: PJ
authors.lastname: Eichhorn
authors.forename: Laura
authors.initials: L
authors.lastname: Rodón
authors.forename: Alba
authors.initials: A
authors.lastname: Gonzàlez-Juncà
authors.forename: Annette
authors.initials: A
authors.lastname: Dirac
authors.forename: Magüi
authors.initials: M
authors.lastname: Gili
authors.forename: Elena
authors.initials: E
authors.lastname: Martínez-Sáez
authors.forename: Claudia
authors.initials: C
authors.lastname: Aura
authors.forename: Ignasi
authors.initials: I
authors.lastname: Barba
authors.forename: Vicente
authors.initials: V
authors.lastname: Peg
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Isabel
authors.initials: I
authors.lastname: Cuartas
authors.forename: Jose
authors.initials: J
authors.lastname: Jimenez
authors.forename: David
authors.initials: D
authors.lastname: García-Dorado
authors.forename: Juan
authors.initials: J
authors.lastname: Sahuquillo
authors.forename: Réné
authors.initials: R
authors.lastname: Bernards
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Joan
authors.initials: J
authors.lastname: Seoane
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D010450:Endopeptidases; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases; C579225:Usp15 protein, mouse