title: Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells.
abstract: CYLD is a deubiquitinating (DUB) enzyme that has a pivotal role in modulating nuclear factor kappa B (NF-κB) signaling pathways by removing the lysine 63- and linear-linked ubiquitin chain from substrates such as tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. Loss of CYLD activity is associated with tumorigenicity, and levels of CYLD are lost or downregulated in different types of human tumors. In the present study, we found that high CYLD expression was associated with better overall survival and relapse-free neuroblastoma patient outcome, as well as inversely correlated with the stage of neuroblastoma. Retinoic acid-mediated differentiation of neuroblastoma restored CYLD expression and promoted SUMOylation of CYLD. This posttranslational modification inhibited deubiquitinase activity of CYLD against TRAF2 and TRAF6 and facilitated NF-κB signaling. Overexpression of non-SUMOylatable mutant CYLD in neuroblastoma cells reduced retinoic acid-induced NF-κB activation and differentiation of cells, but instead promoted cell death.
authors.affiliation: Translational Cancer Research, Division of Molecular Tumor Pathology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Translational Cancer Research, Division of Molecular Tumor Pathology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: K C
authors.initials: KC
authors.lastname: Masoumi
authors.affiliation: Translational Cancer Research, Division of Molecular Tumor Pathology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Massoumi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D000074749:Deubiquitinating Enzyme CYLD; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058207:Sumoylation; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D025521:Tumor Suppressor Proteins; D014212:Tretinoin; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD