Research Progress of DUB Enzyme in Hepatocellular Carcinoma

Abstract

According to GLOBOCAN 2021 cancer incidence and mortality statistics compiled by the International Agency for Research on Cancer, hepatocellular carcinoma (HCC) is the most common malignancy in the human liver and one of the leading causes of cancer death worldwide. Although there have been great advances in the treatment of HCC, such as regofenib, sorafenib, and lomvatinib, which have been developed and approved for the clinical treatment of advanced or metastatic HCC. However, they only prolong survival by a few months, and patients with advanced liver cancer are susceptible to tumor invasion metastasis and drug resistance. Ubiquitination modification is a type of post-translational modification of proteins. It can affect the physiological activity of cells by regulating the localization, stability and activity of proteins, such as: gene transcription, DNA damage signaling and other pathways. The reversible process of ubiquitination is called de-ubiquitination: it is the process of re-releasing ubiquitinated substrates with the participation of de-ubiquitinases (DUBs) and other active substances. There is growing evidence that many dysregulations of DUBs are associated with tumorigenesis. Although dysregulation of deuquitinase function is often found in HCC and other cancers, The mechanisms of action of many DUBs in HCC have not been elucidated. In this review, we focused on several deubiquitinases (DUBs) associated with hepatocellular carcinoma, including their structure, function, and relationship to hepatocellular carcinoma. hepatocellular carcinoma was highlighted, as well as the latest research reports. Among them, we focus on the USP family and OTU family which are more studied in the HCC. In addition, we discussed the prospects and significance of targeting DUBs as a new strategy for the treatment of hepatocellular carcinoma. It also briefly summarizes the research progress of some DUB-related small molecule inhibitors and their clinical application significance as a treatment for HCC in the future.

UCHL3 promotes hepatocellular carcinoma cell migration by de-ubiquitinating and stabilizing Vimentin

“…Indeed, liver cancers, along with pancreatic cancer, generally have low survival rates ( 37 ). Ubiquitin dysregulation, due to imbalances between ubiquitinase and de-ubiquitinase activities, is thought to affect tumor development ( 38 – 40 ), but UCH de-ubiquitinases have been rarely studied in HCC, by contrast with USP enzymes ( 41 ). Only UCH37 has been investigated in liver cancer cells ( 42 ), but other family members may also have an impact.…”

A Novel Scoring Model of Deubiquitination Patterns Predicts Prognosis and Immunotherapeutic Response in Hepatocellular Carcinoma

“…Deubiquitination has a crucial role in tumorigenesis and progression, including cell differentiation, proliferation, metabolism, immunological evasion, and drug resistance, according to accumulating evidence [14] . Dysregulation of deubiquitination is associated with poor prognosis in HCC [19] . Identifying relevant prognostic signatures and formulating immunotherapeutic approaches for HCC may be aided by a deeper comprehension of the roles of various deubiquitination patterns and the characterization of TME infiltration [ 44 , 45 ].…”

“…Numerous DUBs have been shown to be substantially expressed in cancerous tissues, including pancreatic cancer, lung cancer, and liver cancer [16] , [17] , [18] , indicating that deubiquitination is more active in tumours and closely associated with tumour progression. By modulating oncogenic factors such as c-Myc and FoxM1, deubiquitination can promote carcinogenesis and provide novel therapeutic targets in HCC [19] . Multiple investigations have shown that deubiquitination is intimately associated with drug resistance in HCC.…”

CD69 serves as a potential diagnostic and prognostic biomarker for hepatocellular carcinoma

“…The identification of optimal treatment options, personalized therapy as well as rational multidisciplinary interventions are the directions of recent efforts. The pathogenesis of HCC is more complex, and a deep understanding of the molecular mechanisms underlying the pathogenesis of HCC can provide effective therapeutic strategies to improve the survival rate of patients with HCC 9 . Current studies have found that cell deaths are important for inflammatory diseases 10 .…”