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The ubiquitin-specific protease USP2a enhances tumor progression by targeting cyclin A1 in bladder cancer.

The deubiquitinating enzyme USP2a has shown oncogenic properties in many cancer types by impairing ubiquitination of FASN, MDM2, MDMX or Aurora A. Aberrant expression of USP2a has been linked to progression of human tumors, particularly prostate cancer. However, little is known about the role of USP2a or its mechanism of action in bladder cancer. Here, we provide evidence that USP2a is an oncoprotein in bladder cancer cells. Enforced expression of USP2a caused enhanced proliferation, invasion, migration and resistance to several chemotherapeutic reagents, while USP2a loss resulted in slower proliferation, greater chemosensitivity and reduced migratory/invasive capability compared with control cells. USP2a, but not a catalytically inactive mutant, enhanced proliferation in immortalized TRT-HU1 normal human bladder epithelial cells. USP2a bound to cyclin A1 and prevented cyclin A1 ubiquitination, leading to accumulation of cyclin A1 by a block in degradation. Enforced expression of wild type USP2a, but not an inactive USP2a mutant, resulted in cyclin A1 accumulation and increased cell proliferation. We conclude that USP2a impairs ubiquitination and stabilizes an important cell cycle regulator, cyclin A1, raising the possibility of USP2a targeting as a therapeutic strategy against bladder tumors in combination with chemotherapy.

Pubmed ID: 22370483

Authors

  • Kim J
  • Kim WJ
  • Liu Z
  • Loda M
  • Freeman MR

Journal

Cell cycle (Georgetown, Tex.)

Publication Data

March 15, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P50 DK65298
  • Agency: NCI NIH HHS, Id: R01 CA131945
  • Agency: NCI NIH HHS, Id: R01 CA143777
  • Agency: NIDDK NIH HHS, Id: R01 DK087806

Mesh Terms

  • Apoptosis
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cyclin A1
  • Disease Progression
  • Endopeptidases
  • Enzyme Activation
  • Epithelial Cells
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Neoplasm Invasiveness
  • Oncogene Proteins
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Stability
  • Proteolysis
  • RNA Interference
  • Transfection
  • Ubiquitination
  • Urinary Bladder Neoplasms