The deubiquitinase otubain 2 (OTUB2) has been reported to play significant roles in the tumorigenesis of several cancers, but the role of OTUB2 in liver cancer is not investigated yet. In the present study, OTUB2 was found significantly upregulated in liver cancer tumor tissues and cell lines, and elevated OTUB2 indicated as a negative index for the overall survival of liver cancer patients. At the cellular level, knockdown of OTUB2 markedly inhibited liver cancer cell growth. Our further investigations revealed that knockdown of OTUB2 significantly suppressed NF‐κB‐driving luciferase activity, and markedly inhibited the phosphorylation of NF‐κB p65 in liver cancer cells, which indicated that OTUB2 mediated liver cancer cell growth by regulating NF‐κB signaling. Additionally, we found that liver cancer cell lines harboring higher OTUB2 expression were more sensitive to NF‐κB inhibitors, and overexpression of OTUB2 could significantly reduce the antitumor effects of NF‐κB inhibitors in liver cancer cells. This study indicated that OTUB2 could be a promising target for the treatment of liver cancer in the future.

Ubiquitin‐specific peptidase 13 (USP13) has been reported to be involved in the tumorigenesis of several tumors, but its function in tumors is still controversial. In this study, the function of USP13 in hepatocellular carcinoma (HCC) was investigated, and we found that USP13 was significantly upregulated in both of primary HCC tumor tissues and cell lines. And HCC patients with high USP13 expression had a shorter overall survival or relapse‐free survival than patients with low USP13 expression. In HCC cell lines, knockdown of USP13 by shRNAs markedly decreased HCC cell growth, and mechanistic investigations revealed that USP13 knockdown could markedly downregulate the expression levels of c‐Myc. Moreover, overexpression of c‐Myc could significantly attenuate the effects of shUSP13 on HCC cell growth inhibition. In addition, in vivo experiments showed that knockdown of USP13 could significantly inhibit xenograft tumor growth of HCC. Taken together, our present study provided the first evidence that USP13 acted as a novel driver in HCC tumorigenesis by regulating c‐Myc expression, and targeting USP13 could be a promising strategy for HCC therapy.