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Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

Oncogene volume 34, pages 2251–2260 (2015)Cite this article

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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.

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Acknowledgements

The plasmid for mammalian expression of His-SUMO1, His-SUMO2 and MYC-SUMO1 plasmids were a kind gift from Dr Frauke Melchior (ZMBH, Heidelberg, Germany). Flag-TRAF2 and Flag-TRAF6 plasmids were a kind gift from Dr René Bernards (The Netherlands Cancer Institute, Amsterdam, The Netherlands). We thank Dr Ingrid Ora for her critical reading of this manuscript. This work was supported by the Swedish Cancer Foundation, the Swedish Medical Research Council, the Royal Physiographic Society in Lund, the Gunnar Nilsson Foundations, the Gyllenstiernska Krapperupps Foundations, the BioCARE and by funding from the European Research Council (ERC), under the European Union’s Seventh Framework Programme for Research and Technology Development (grant agreement no. 260460, awarded to RM).

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  1. Division of Molecular Tumor Pathology, Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund, Sweden

    T Kobayashi, K C Masoumi & R Massoumi

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  1. T Kobayashi
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Correspondence to R Massoumi.

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Kobayashi, T., Masoumi, K. & Massoumi, R. Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells. Oncogene 34, 2251–2260 (2015). https://doi.org/10.1038/onc.2014.159

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