Abstract
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‐β (TGF‐β) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF‐β 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‐β 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.
Highlights
Hepatocellular carcinoma (HCC) has emerged as the fifth most frequently diagnosed cancer and the second leading cause of cancer-related deaths worldwide, especially in South Africa and East Asia (Haider et al, 2019; Kim et al, 2018; Wang et al, 2019)
Since Smad4, the only co-Smad of transforming growth factor-b (TGF-b) signaling, plays a critical role in the migration and the transcriptional activity of Smad complexes (Fig. 1A– C), we sought to investigate the contribution of ubiquitinspecific proteases (USPs) involved in Smad4 regulation
The results showed that siRNA pools for eight USPs including USP7, USP10, USP11, USP21, USP26, USP29, USP33, and USPL1 could remarkably inhibited TGF-b responses (Fig. 1D, relative luciferase activity < 0.5)
Summary
Hepatocellular carcinoma (HCC) has emerged as the fifth most frequently diagnosed cancer and the second leading cause of cancer-related deaths worldwide, especially in South Africa and East Asia (Haider et al, 2019; Kim et al, 2018; Wang et al, 2019). The key reasons for the high mortality rate of HCC are diagnosis at an advanced stage and intrahepatic/extrahepatic metastasis; most of patients often diagnosed at advanced, unresectable, or metastatic HCC; and just a minority of patients is diagnosed at an early stage (Haider et al, 2019; L’Hermitte et al, 2019; Yuan et al, 2014; Zhu et al, 2018). Treatment strategies for Abbreviations DUB, deubiquitinating enzyme; EMT, epithelial–mesenchymal transition; HCC, hepatocellular carcinoma; rhUSP10, bacterial-expressed recombinant human USP10; TGFBR I, type I serine/threonine kinase receptors; TGFBR II, type II serine/threonine kinase receptors; TGF-b, transforming growth factor-b; USPs, ubiquitin-specific proteases.
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