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

  • Nat Med. 2012 Feb 19;18(3):429-35. doi: 10.1038/nm.2619.
Pieter J A Eichhorn  1 ,  Laura Rodón ,  Alba Gonzàlez-Juncà ,  Annette Dirac ,  Magüi Gili ,  Elena Martínez-Sáez ,  Claudia Aura ,  Ignasi Barba ,  Vicente Peg ,  Aleix Prat ,  Isabel Cuartas ,  Jose Jimenez ,  David García-Dorado ,  Juan Sahuquillo ,  Réné Bernards ,  José Baselga ,  Joan Seoane
Affiliations
  • 1. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
PMID: 22344298 DOI: 10.1038/nm.2619
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.