title: Ubiquitin-specific protease 2 decreases p53-dependent apoptosis in cutaneous T-cell lymphoma.
abstract: Treatment of advanced cutaneous T-cell lymphomas (CTCL) is challenging because they are resistant to conventional chemotherapy. USP2 has been shown to promote resistance to chemotherapeutic agents in several cancer models.We show here USP2 is expressed in quiescent and activated T-cells and its expression is 50% lower in CTCL cell lines (MyLa2000, SeAx and Hut-78) than in normal T-cells. USP2 is expressed in neoplastic cells in early, plaque-stage mycosis fungoides (MF) and is downregulated in advanced tumor stages. Upon treatment with psoralen with UVA (PUVA) or a p53 activator, nutlin3a, USP2 expression is significantly increased in MyLa2000 (p53wt/wt), but not in SeAx (p53mut) or Hut-78 (p53-/-). USP2 knockdown decreases MyLa2000 cell viability after PUVA by 50% but not Hut-78, suggesting that the function of USP2 in CTCL cells is p53-dependent. Furthermore, USP2 knockdown results in a decreased Mdm2 expression and upregulation of p53. Taken together, our findings suggest that USP2 stabilizes Mdm2 which antagonizes pro-apoptotic activity of p53 and possibly contributes to therapeutic resistance in CTCL.
authors.affiliation: Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.
authors.forename: Tianling
authors.initials: T
authors.lastname: Wei
authors.affiliation: Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.
authors.forename: Edyta
authors.initials: E
authors.lastname: Biskup
authors.affiliation: Department of Pathology, Zealand University Hospital, Køge, Denmark.
authors.forename: Lise Mette Rahbek
authors.initials: LM
authors.lastname: Gjerdrum
authors.affiliation: Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.
authors.forename: Omid
authors.initials: O
authors.lastname: Niazi
authors.affiliation: Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark.|Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Ødum
authors.affiliation: Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.|Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Robert
authors.initials: R
authors.lastname: Gniadecki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase
keywords: PUVA; cutaneous T-cell lymphoma; ubiquitin-specific protease 2