Ubiquitin-specific protease 2 decreases p53-dependent apoptosis in cutaneous T-cell lymphoma

Abstract

// Tianling Wei 1 , Edyta Biskup 1 , Lise Mette Rahbek Gjerdrum 2 , Omid Niazi 1 , Niels Ødum 3, 4 , Robert Gniadecki 1, 4 1 Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark 2 Department of Pathology, Zealand University Hospital, Køge, Denmark 3 Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark 4 Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark Correspondence to: Tianling Wei, email: weitianling@gmail.com Keywords: ubiquitin-specific protease 2, cutaneous T-cell lymphoma, PUVA Received: October 26, 2015      Accepted: June 09, 2016      Published: June 24, 2016 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 (p53 wt/wt ), but not in SeAx (p53 mut ) 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.