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

Pieter J.A. Eichhorn | Zendy; Laura Rodón | Zendy; Alba Gonzàlez-Juncà | Zendy; Annette M.G. Dirac | Zendy; Magüi Gili | Zendy; Elena MartínezSáez | Zendy; Claudia Aura | Zendy; Ignasi Barba | Zendy; Vicente Peg | Zendy; Aleix Prat | Zendy; Isabel Cuartas | Zendy; José Jimenez | Zendy; David Garcı́a-Dorado | Zendy; Juan Sahuquillo | Zendy; René Bernards | Zendy; José Baselga | Zendy; Joan Seoane | Zendy

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

Author(s) -

Pieter J.A. Eichhorn,

Laura Rodón,

Alba Gonzàlez-Juncà,

Annette M.G. Dirac,

Magüi Gili,

Elena MartínezSáez,

Claudia Aura,

Ignasi Barba,

Vicente Peg,

Aleix Prat,

Isabel Cuartas,

José Jimenez,

David Garcı́a-Dorado,

Juan Sahuquillo,

René Bernards,

José Baselga,

Joan Seoane

Publication year - 2012

Publication title -

nature medicine

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 19.536

H-Index - 547

eISSN - 1546-170X

pISSN - 1078-8956

DOI - 10.1038/nm.2619

Subject(s) - cancer research , transforming growth factor , signal transduction , smad , downregulation and upregulation , deubiquitinating enzyme , ubiquitin ligase , signal transducing adaptor protein , tgf beta receptor 2 , biology , carcinogenesis , r smad , ubiquitin , receptor , microbiology and biotechnology , cancer , growth factor , tgf alpha , gene , biochemistry , genetics

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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