title: The ubiquitin-specific protease USP2a enhances tumor progression by targeting cyclin A1 in bladder cancer.
abstract: 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.
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Jayoung.Kim@cshs.org
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Liu
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056750:Cyclin A1 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D014162:Transfection; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C503745:CCNA1 protein, human; D056750:Cyclin A1; D015513:Oncogene Proteins; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase