Abstract
Deubiquitinases (DUBs) play essential roles in normal cell proliferation and tumor growth. However, the molecular mechanisms of DUBs on hepatocellular carcinoma (HCC) remains largely unknown. In this study, based on analysis of several HCC datasets, we found that the USP21 gene, which encodes a member of the ubiquitin-specific protease family, is highly amplified and overexpressed in HCCs, with the extent of this up-regulation significantly correlating with poor clinical outcomes. Inhibition of USP21 in HCC cell lines decreased cell proliferation, anchorage-independent growth, cell cycle progression, and in vivo tumor growth. Conversely, ectopic expression of USP21 transformed the normal human hepatocyte line HL-7702 and increased the tumorigenicity of the HCC cell line MHCC97L. Mechanistically, USP21 stabilized MEK2 by decreasing its polyubiquitination at Lys48, thereby activating the ERK signaling pathway. Importantly, MEK2 partially mediated the optimal expression of USP21-mediated oncogenic phenotypes. These findings indicate that USP21-mediated deubiquitination and stabilization of MEK2 play a critical role in HCC development.
Highlights
Liver cancer is the fifth most common cancer worldwide and the leading cause of cancer death, with an estimated annual incidence of 782,500 new patients and 745,500 deaths[1,2]
USP21 is highly expressed in Hepatocellular carcinoma (HCC) and associated with poor survival in HCC patients To search for driver DUBs in HCC, we downloaded several HCC datasets and analyzed ubiquitin specific proteases (USPs) expression profiles
In the current work, we have determined that ubiquitinspecific protease USP21 is amplified and upregulated in HCC and that this is inversely correlated with patient survival in two different large patient groups
Summary
Liver cancer is the fifth most common cancer worldwide and the leading cause of cancer death, with an estimated annual incidence of 782,500 new patients and 745,500 deaths[1,2]. Hepatocellular carcinoma (HCC) accounts for ~70–90% of all primary liver cancer, and it is among the most common visceral neoplasms[3,4]. Hepatitis B and C virus infections are two major risk factors for HCC, while other risk factors include aflatoxin, type 2 diabetes, alcoholic and non-alchoholic cirrhosis, fatty liver disease, and tobacco consumption[5]. Surgical resection, transplantation, and percutaneous ablation are the most common treatments for patients with early-stage HCC6. Two important clinical features of HCC are its heterogeneity and its high rate of recurrence[7]. The survival rate of patients with HCC is very low (about 2–7%)
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