Knockdown of ubiquitin‐specific peptidase 13 inhibits cell growth of hepatocellular carcinoma by reducing c‐Myc expression

Abstract

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.

Identification and Validation of Ubiquitin-Specific Proteases as a Novel Prognostic Signature for Hepatocellular Carcinoma

“…In accordance with the data in cases at different grades, USP39 displayed a dynamic increasing from pre-HCC status to HCC. However, USP13, USP22, and USP39, previously correlated with the malignant phenotypes of HCC cells (26)(27)(28), showed less differences among the sub-groups. It could be speculated that these USPs might be not key driver genes for HCC progression though they enhance aggressive behaviors of HCC cells.…”

Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma

“…Ubiquitin specific protease 13 (USP13), which belongs to the deubiquitinating enzymes (DUBs) superfamily, is implicated in the occurrence and progression of human cancer via promoting deubiquitination and stabilization of substrate proteins, including myeloid cell leukemia 1 (MCL1) (Zhang et al, 2018), phosphatase and tensin homolog (PTEN) (Zhang et al, 2013), melanocyte inducing transcription factor (MITF) (Zhao et al, 2011), Myc (Fang et al, 2017), USP10 (Liu et al, 2011), and RAP80 (Li et al, 2017). A recent study presents that USP13 silencing represses HCC growth possibly by decreasing Myc expression (Huang et al, 2020). Nevertheless, whether USP13 contributes to HCC progression by regulating the toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB (TLR4/MyD88/NF-κB) pathway remains unclear.…”

USP13: Multiple Functions and Target Inhibition

“…The c-Myc gene encodes a proto-oncoprotein, a widely recognized transcription factor regulating approximately 10–15% of genes implicated in cell proliferation, differentiation, apoptosis and other processes ( Friedman et al, 2017 ; Habib et al, 2020 ), and c-Myc mutations are often associated with tumors ( Berns et al, 1997 ; Brodsky and McCracken, 1999 ; Hermeking et al, 2000 ; Morrish et al, 2003 ; Wilson et al, 2004 ). Recently, it has been reported that USP13 is co-overexpressed with c-Myc in many tumors, such as NSCLC ( Wu et al, 2019 ), cholangiocarcinoma (CAA) ( Zhou et al, 2020 ), GSCs ( Fang et al, 2017 ), and hepatocellular carcinoma (HCC) ( Huang et al, 2020 ). Consistently, knockdown or pharmacological inhibition of USP13 antagonized tumor cell growth.…”

“…For example, in non-small-cell lung cancer, downregulation of USP13 suppresses ATK/MAPK signaling, reducing c-Myc protein levels and retards tumor growth both in tumor cells and nude mice ( Wu et al, 2019 ). In cholangiocarcinoma, TGF-β signaling triggers the phosphorylation of CLK3, a serine/threonine kinase that directly phosphorylates USP13 at Y708 and facilitates USP13 interaction with c-Myc ( Zhou et al, 2020 ); in GSCs, USP13 can enhance the stability through deubiquitinating c-Myc, activating purine synthesis mediated by c-Myc and inducing the tumorigenesis of GSCs ( Fang et al, 2017 ); in hepatocellular carcinoma, knockdown of USP13 by shRNA can markedly downregulate c-Myc expression, resisting xenograft tumor growth of HCC ( Huang et al, 2020 ). Hence, inhibition of USP13 might be beneficial for related cancer treatment.…”