Kobayashi T, Masoumi K C, Massoumi R
Translational Cancer Research, Division of Molecular Tumor Pathology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Oncogene. 2015 Apr 23;34(17):2251-60. doi: 10.1038/onc.2014.159. Epub 2014 Jun 9.
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.
CYLD是一种去泛素化（DUB）酶，通过从肿瘤坏死因子受体相关因子2（TRAF2）和TRAF6等底物上移除赖氨酸63连接和线性连接的泛素链，在调节核因子κB（NF-κB）信号通路中起关键作用。CYLD活性丧失与肿瘤发生相关，在不同类型的人类肿瘤中，CYLD水平降低或缺失。在本研究中，我们发现CYLD高表达与神经母细胞瘤患者更好的总生存期和无复发生存期相关，且与神经母细胞瘤分期呈负相关。视黄酸介导的神经母细胞瘤分化可恢复CYLD表达并促进CYLD的SUMO化。这种翻译后修饰抑制了CYLD对TRAF2和TRAF6的去泛素酶活性，并促进了NF-κB信号传导。在神经母细胞瘤细胞中过表达不可SUMO化的突变型CYLD可降低视黄酸诱导的NF-κB激活和细胞分化，但反而促进细胞死亡。
