State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Oncology, Huashan Hospital Fudan University, Shanghai, China.
Exp Cell Res. 2019 Jan 15;374(2):304-314. doi: 10.1016/j.yexcr.2018.12.001. Epub 2018 Dec 4.
E3 ubiquitin ligases, which are key enzymes in the ubiquitin proteasome system, catalyze the ubiquitination of proteins to target them for proteasomal degradation. Emerging evidence suggests that E3 ubiquitin ligases play important roles in the development and progression of lung cancer. In our study, we characterized the gene expression landscape of lung cancer using data obtained from TCGA to explore the changes in E3 ubiquitin ligase containing the regulators of E3 ubiquitin ligase activity. Overall, most gene expression changes occurred in NSCLC tissues compared with adjacent normal ones. In total, 48 E3 ubiquitin ligases containing the regulators were up-regulated in NSCLC tissues compared with their levels in normal tissues. We analyzed the expression of up-regulated E3 ubiquitin ligases containing the regulators in two publicly available transcriptome data sets (GSE13213 and GSE30219). We found that four E3 ubiquitin ligases (UHRF1, BRCA1, TRAIP and HLTF) and one regulator of ubiquitin E3 activity DCUN1D1 that were dramatically up-regulated in cancer were significantly associated with tumor metastasis and patient's poor prognosis both in two transcriptome data sets. Next, clinical analysis indicated that the expression levels of DCUN1D1 correlated with clinical stage and lymph node metastasis in NSCLC patients as determined by quantitative reverse transcription-PCR. Furthermore, functional assays showed that DCUN1D1 promoted NSCLC cell invasion and migration as determined by transwell assay in vitro. Mechanistically, we found that the C-terminal Cullin binding domain leads to oncogenic activity and the UBA domain acts as a negative regulator of DCUN1D1 function in NSCLC. Moreover, DCUN1D1 activated the FAK oncogenic signaling pathway and up-regulated PD-L1. Taken together, our results demonstrate that DCUN1D1 is a metastasis regulator and suggest a new therapeutic option for NSCLC metastasis.
E3 泛素连接酶是泛素蛋白酶体系统中的关键酶，可催化蛋白质的泛素化，将其靶向蛋白酶体降解。有研究表明，E3 泛素连接酶在肺癌的发生和发展中发挥着重要作用。在本研究中，我们利用 TCGA 获得的数据对肺癌的基因表达谱进行了特征分析，以探讨 E3 泛素连接酶活性调节因子的变化情况。总的来说，与邻近正常组织相比，非小细胞肺癌（NSCLC）组织中大多数基因表达发生了改变。与正常组织相比，NSCLC 组织中共有 48 个 E3 泛素连接酶活性调节因子上调。我们分析了两个公开的转录组数据集（GSE13213 和 GSE30219）中上调的 E3 泛素连接酶活性调节因子的表达情况。结果发现，四个 E3 泛素连接酶（UHRF1、BRCA1、TRAIP 和 HLTF）和一个 E3 泛素活性调节因子 DCUN1D1 在癌症中显著上调，在两个转录组数据集中均与肿瘤转移和患者不良预后显著相关。接下来，临床分析表明，通过实时定量逆转录聚合酶链反应（qRT-PCR）检测，DCUN1D1 的表达水平与 NSCLC 患者的临床分期和淋巴结转移相关。此外，功能实验表明，通过体外 Transwell 实验，DCUN1D1 促进了 NSCLC 细胞的侵袭和迁移。机制上，我们发现 C 端 Cullin 结合域导致致癌活性，UBA 结构域在 NSCLC 中作为 DCUN1D1 功能的负调节因子。此外，DCUN1D1 激活了 FAK 致癌信号通路并上调了 PD-L1。综上所述，我们的研究结果表明，DCUN1D1 是一种转移调节因子，为 NSCLC 转移提供了新的治疗选择。
