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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Brain Neoplasms / genetics
-
Brain Neoplasms / metabolism*
-
Cell Line, Tumor
-
Cell Transformation, Neoplastic / genetics
-
Cell Transformation, Neoplastic / metabolism*
-
Disease Models, Animal
-
Endopeptidases / genetics*
-
Endopeptidases / metabolism*
-
Gene Expression Regulation, Neoplastic
-
Glioblastoma / genetics
-
Glioblastoma / metabolism*
-
HEK293 Cells
-
Humans
-
Magnetic Resonance Imaging
-
Mice
-
Phosphorylation
-
Prognosis
-
Protein Serine-Threonine Kinases / genetics*
-
Protein Serine-Threonine Kinases / metabolism*
-
RNA Interference
-
Receptor, Transforming Growth Factor-beta Type I
-
Receptors, Transforming Growth Factor beta / genetics*
-
Receptors, Transforming Growth Factor beta / metabolism*
-
Signal Transduction
-
Smad2 Protein / genetics
-
Smad2 Protein / metabolism
-
Smad7 Protein / metabolism
-
Transforming Growth Factor beta / genetics
-
Transforming Growth Factor beta / metabolism*
-
Ubiquitin
-
Ubiquitin-Protein Ligases / metabolism
-
Ubiquitin-Specific Proteases
Substances
-
Receptors, Transforming Growth Factor beta
-
SMAD7 protein, human
-
Smad2 Protein
-
Smad7 Protein
-
Transforming Growth Factor beta
-
Ubiquitin
-
SMURF2 protein, human
-
Ubiquitin-Protein Ligases
-
Protein Serine-Threonine Kinases
-
Receptor, Transforming Growth Factor-beta Type I
-
Endopeptidases
-
USP15 protein, human
-
Ubiquitin-Specific Proteases
-
Usp15 protein, mouse