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

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.
Mesh Terms:
Animals, Brain Neoplasms, Cell Line, Tumor, Cell Transformation, Neoplastic, Disease Models, Animal, Endopeptidases, Gene Expression Regulation, Neoplastic, Glioblastoma, HEK293 Cells, Humans, Magnetic Resonance Imaging, Mice, Phosphorylation, Prognosis, Protein-Serine-Threonine Kinases, RNA Interference, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad2 Protein, Smad7 Protein, Transforming Growth Factor beta, Ubiquitin, Ubiquitin-Protein Ligases
Nat. Med.
Date: Mar. 01, 2012
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