Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein
Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein
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去泛素化酶USP10通过去泛素化和稳定Smad4蛋白促进肝细胞癌转移
DOI：
10.1002/1878-0261.12596
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发表时间：
2019-11-27
影响因子：
6.6
通讯作者：
Zhu, Hong
中科院分区：
文献类型：
--
作者：
Yuan, Tao;Chen, Zibo;Zhu, Hong
肝细胞癌已成为最常见的威胁生命的癌症之一，其高死亡率在很大程度上是由于肿瘤的转移所致。Smad4和转化生长因子-β的持续激活与晚期肝细胞癌的转移密切相关。然而，Smad4和转化生长因子-β途径异常激活的调控机制仍然不清楚。在本研究中，通过对USPS siRNA文库的功能筛选，我们发现USP10是一种脱泛素化酶(DUB)，它维持Smad4的蛋白水平并激活转化生长因子-β信号。进一步的分析表明，USP10直接与Smad4相互作用，并通过其蛋白水解性泛素化的切割来稳定Smad4，从而促进肝癌转移。ShRNAs或催化抑制剂Spautin-1对USP10的抑制显著抑制了肝癌细胞的迁移，而Smad4的重组则能有效地修复这一缺陷。总之，我们的研究不仅揭示了USP10对Smad4蛋白丰度的调节作用，而且表明USP10可以作为Smad4阳性患者转移性肝癌的潜在干预靶点。
Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life-threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor-beta (TGF-beta) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF-beta pathway remains elusive. In this study, using a functional screen of USPs siRNA library, we identified ubiquitin-specific proteases USP10 as a deubiquitinating enzyme (DUB) that sustains the protein level of Smad4 and activates TGF-beta signaling. Further analysis showed that USP10 directly interacts with Smad4 and stabilizes it through the cleavage of its proteolytic ubiquitination, thus promoting HCC metastasis. The suppression of USP10 by either shRNAs or catalytic inhibitor Spautin-1 significantly inhibited the migration of HCC cells, whereas the reconstitution of Smad4 was able to efficiently rescue this defect. Overall, our study not only uncovers the regulatory effect of USP10 on the protein abundance of Smad4, but also indicates that USP10 could be regarded as a potential intervention target for the metastatic HCC in Smad4-positive patients.