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.

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