USP33 regulates c-Met expression by deubiquitinating SP1 to facilitate metastasis in hepatocellular carcinoma
USP33 regulates c-Met expression by deubiquitinating SP1 to facilitate metastasis in hepatocellular carcinoma
复制标题
USP33通过去泛素化SP1来调节c-Met表达以促进肝细胞癌的转移
DOI：
10.1016/j.lfs.2020.118316
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发表时间：
2020-11-15
期刊：
影响因子：
6.1
通讯作者：
Hu, Guohui
中科院分区：
文献类型：
--
作者：
Gan, Qin;Shao, Jia;Hu, Guohui
目的：去泛素化酶泛素特异性蛋白酶33（USP 33）在多种肿瘤中异常表达，并参与肿瘤的进展。主要方法：采用免疫组化、Western blotting和qRT-PCR方法检测USP 33在肝细胞癌（HCC）中的表达。然后我们分析了USP 33表达对HCC预后的影响。进一步探讨USP 33在体外调节HCC细胞迁移和侵袭中的作用。进行动物研究以研究USP 33对肿瘤转移的影响。RNA测序和荧光素酶报告和免疫荧光分析被用来识别特异性蛋白1（SP1）/c-Met axills.Key的发现：在这里，我们第一次报告了在HCC组织中USP 33的表达异常增加，USP 33可以作为HCC患者的预后生物标志物。我们发现，USP 33基因敲低抑制肝癌细胞的侵袭和转移在体外和体内，这是部分依赖于c-Met。进一步的研究表明，USP 33通过增强转录因子SP1在HCC细胞中的蛋白稳定性来调节c-Met的表达。从机制上讲，USP 33直接结合SP1并降低其泛素化，从而上调c-Met表达。意义：我们的研究结果表明，USP 33作为SP1的去泛素化酶，通过激活SP1/c-Met轴促进HCC的侵袭和转移。这些数据表明USP 33的一个以前未知的功能，这可能为HCC患者的治疗提供潜在的靶点。
Aims: Deubiquitinase ubiquitin-specific protease 33 (USP33) is abnormally expressed in various tumors and participates in tumor progression. However, the expression and biological role of USP33 in hepatocellular carcinoma (HCC) are still unclear.Main methods: We performed immunohistochemistry, western blotting, and qRT-PCR analysis to determine the expression of USP33 in HCC. We then analyzed the effects of USP33 expression on the prognosis of HCC. The roles of USP33 in regulating HCC cell migration and invasion were further explored in vitro. Animal studies were performed to investigate the effects of USP33 on tumor metastasis. RNA sequencing and luciferase reporter and immunofluorescence assays were used to identify the activation of the specificity protein 1 (SP1)/c-Met axis.Key findings: Here, for the first time, we reported an abnormal increase in the expression of USP33 in HCC tissues and that USP33 may act as a prognostic biomarker for HCC patients. We found that USP33 knockdown inhibited the invasion and metastasis in HCC cells both in vitro and in vivo, which was partly dependent on c-Met. Further investigations revealed that USP33 regulated c-Met expression by enhancing the protein stability of the transcription factor SP1 in HCC cells. Mechanistically, USP33 directly bound SP1 and decreased its ubiquitination, thereby upregulating c-Met expression.Significance: Our results reveal that USP33 acts as the deubiquitinating enzyme of SP1 and contributes to HCC invasion and metastasis through activation of the SP1/c-Met axis. These data indicate a previously unknown function of USP33, which may provide potential targets for the treatment of HCC patients.