USP10 Promotes Proliferation of Hepatocellular Carcinoma by Deubiquitinating and Stabilizing YAP/TAZ

Abstract

Yes-associated protein (YAP) and its paralogue, transcriptional co-activator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma (HCC). However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in HCC remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in HCC models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB. Mechanistically, USP10 directly interacted with and stabilized YAP/TAZ by reverting their proteolytic ubiquitination. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ, promoted their proteasomal degradation, and ultimately arrested the proliferation of HCC in vitro and in vivo. Expression levels of USP10 positively correlated with the abundance of YAP/TAZ in HCC patient samples as well as in N-nitrosodiethylamine (DEN)-induced liver cancer mice models. Collectively, this study establishes the causal link between USP10 and hyperactivated YAP/TAZ in HCC cells and provides a rationale for potential therapeutic interventions in the treatment of HCC patients harboring a high level of YAP/TAZ. Significance: These findings identify USP10 as a DUB of YAP/TAZ and its role in HCC progression, which may serve as a potential therapeutic target for HCC treatment.

Serine Metabolism Regulates YAP Activity Through USP7 in Colon Cancer

“…Ubiquitinspecific proteases (USPs) have been identified as one family of approximately 100 DUBs (Mevissen and Komander, 2017 cancers (Kim et al, 2016;Li et al, 2018;Zhu et al, 2018). The abundance of YAP and TAZ was potently increased by USP10, which removed their poly-ubiquitin chains directly in HCC (Zhu et al, 2020). Evidence has accumulated to show that USP7 plays opposing roles in tumorigenesis because its function is dependent on context (Li et al, 2002;Zhan et al, 2017).…”

Comprehensive analysis of ubiquitin‐specific protease 1 reveals its importance in hepatocellular carcinoma

“…USP7 regulates the Hippo pathway by deubiquitinating Yorkie and predicts the prognosis of HCC 56,57 . USP10 maintains the activity of Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ), stabilizes Smad4 protein and then promotes the proliferation of HCC 58,59 . However, to our knowledge, few studies have investigated the role of USP1 in liver cancer.…”

“…51,52 In recent years, our understanding of deubiquitinases has made great progress, espe- of HCC. 58,59 However, to our knowledge, few studies have investigated the role of USP1 in liver cancer. Considering the importance of USP1 in regulating DNA repair, it has long been considered a potential therapeutic target for tumours.…”

Hypermethylation of LATS2 Promoter and Its Prognostic Value in IDH-Mutated Low-Grade Gliomas

“…Intriguingly, we found that BTRC, an E3 ligase responsible for YAP degradation (Zhao et al, 2010), was dramatically upregulated in LGG compared to GBM ( Figure 4G). On the other hand, several reported deubiquitinases for YAP (Li et al, 2018;Sun et al, 2019;Pan et al, 2020;Zhu et al, 2020) were also upregulated ( Supplementary Figure 4). Thus, further work is needed to dissect the mechanism(s) for the loss of YAP protein expression in LGG.…”