A review of deubiquitinases and thier roles in tumorigenesis and development

Liang, Xian-Wen; Wang, Sheng-Zhong; Liu, Bing; Chen, Jia-Cheng; Cao, Zhi; Chu, Feng-Ran; Lin, Xiong; Liu, Hui; Wu, Jin-Cai

doi:10.3389/fbioe.2023.1204472

Cited by 7 publications

(6 citation statements)

References 124 publications

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“…The regulation of ubiquitination is a reversible process that is constantly mediated by different E3 ubiquitin ligases and DUBs [ 42 ]. Accumulating evidence has showed that DUBs play an indispensable role in the occurrence and progression of cancers [ 43 – 47 ]. However, the potential roles of DUBs in HCC are largely unknown.…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis

Tang

Long

et al. 2023

Cell Commun Signal

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Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal human malignancies, and with quite limited treatment alternatives. The proteasome is responsible for most of the protein degradation in eukaryotic cells and required for the maintenance of intracellular homeostasis. However, its potential role in HCC is largely unknown. In the current study, we identified eukaryotic translation initiation factor 3 subunit H (EIF3H), belonging to the JAB1/MPN/MOV34 (JAMM) superfamily, as a bona fide deubiquitylase of O-GlcNAc transferase (OGT) in HCC. We explored that EIF3H was positively associated with OGT in HCC and was related to the unfavorable prognosis. EIF3H could interact with, deubiquitylate, and stabilize OGT in a deubiquitylase-dependent manner. Specifically, EIF3H was associated with the GT domain of ERα via its JAB/MP domain, thus inhibiting the K48-linked ubiquitin chain on OGT. Besides, we demonstrated that the knockdown of EIF3H significantly reduced OGT protein expression, cell proliferation and invasion, and caused G1/S arrest of HCC. We also found that the deletion of EIF3H prompted ferroptosis in HCC cells. Finally, the effects of EIF3H depletion could be reversed by further OGT overexpression, implying that the OGT status is indispensable for EIF3H function in HCC carcinogenesis. In summary, our study described the oncogenic function of EIF3H and revealed an interesting post-translational mechanism between EIF3H, OGT, and ferroptosis in HCC. Targeting the EIF3H may be a promising approach in HCC.

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Section: Discussionmentioning

confidence: 99%

The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis

Tang

Long

et al. 2023

Cell Commun Signal

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“…The overexpression of members of the ubiquitin system, as well as the expression of their mutant proteins, has been reported in several cancer types, where they correlate with malignant progression, poor survival and prognosis [ 107 , 108 , 109 ]. Since the activity or proteolysis of several oncoproteins and tumor-suppressor proteins is impaired by the deregulation of the ubiquitin system in cancer [ 48 ], numerous biological processes are altered, including the cell cycle [ 15 , 51 , 110 ], cell invasion and metastasis [ 110 , 111 ], cancer metabolism [ 112 , 113 ], cancer stem cell stemness [ 113 , 114 ], immunological tumor microenvironment [ 113 ], immune evasion [ 51 ], tumor-promoting inflammation [ 51 ] and evasion from apoptosis [ 51 , 110 ].…”

Section: Aberrant Ubiquitination In Cancermentioning

confidence: 99%

“…Defects in deubiquitination have effects on the NF-kB, AKT and BRCA signaling pathways [ 119 ]. For a more comprehensive description of the role of the ubiquitination system in cancer development and progression, readers are referred to specific reviews [ 15 , 51 , 110 , 111 , 112 , 113 , 114 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ].…”

Section: Aberrant Ubiquitination In Cancermentioning

confidence: 99%

“…In the last decades, a large number of drugs/molecules targeting the ubiquitination machinery have entered clinical trials against solid and hematological malignancies (for a review, the reader is referred to [ 51 , 110 , 122 , 125 , 126 , 152 , 153 ]) and several trials have been conducted and are currently ongoing to assess their safety, tolerability and therapeutic activity in cancer ( ). Within this growing number of trials, only a few have been completed and results are currently available ( Table 2 ).…”

Section: Targeting Ubiquitination As a Therapeutic Approach To Cancer...mentioning

confidence: 99%

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Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

Spano,

Catara

2023

Cells

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Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects on various signaling pathways. Ubiquitination can alter the molecular functions of tagged substrates with respect to protein turnover, biological activity, subcellular localization or protein–protein interaction. As a result, a wide variety of cellular processes are under ubiquitination-mediated control, contributing to the maintenance of cellular homeostasis. It follows that the dysregulation of ubiquitination reactions plays a relevant role in the pathogenic states of human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, the enzymes of the ubiquitin–proteasome system (UPS), including E3 ubiquitin ligases and deubiquitinases (DUBs), have attracted attention as novel druggable targets for the development of new anticancer therapeutic approaches. This perspective article summarizes the peculiarities shared by the enzymes involved in the ubiquitination reaction which, when deregulated, can lead to tumorigenesis. Accordingly, an overview of the main pharmacological interventions based on targeting the UPS that are in clinical use or still in clinical trials is provided, also highlighting the limitations of the therapeutic efficacy of these approaches. Therefore, various attempts to circumvent drug resistance and side effects as well as UPS-related emerging technologies in anticancer therapeutics are discussed.

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“…Depending on the type of polyubiquitin chain formed, ubiquitination can direct the substrate to multiprotein complexes or target it for degradation via proteasomes 8 . This process is dynamic and reversible relying on deubiquitinases to remove ubiquitin and stabilize substrate proteins 9 . In the context of cancer development, ubiquitination plays a pivotal role, such as angiogenesis, apoptosis, metastasis, and immunity through its diverse effects on transcription, post-translation modifications, and protein levels 8 .…”

Section: Introductionmentioning

confidence: 99%

Prognostic and Immune Landscape Analysis of Ubiquitination-related Genes in Hepatocellular Carcinoma: Based on Bulk and Single-cell RNA Sequencing Data

Yuan,

Zhu,

et al. 2024

J. Cancer

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Background: Despite significant advances in tumor immunotherapy, hepatocellular carcinoma (HCC) remains a malignancy with a challenging prognosis. The increasing research emphasizes the crucial role of ubiquitination in tumor immunotherapy. However, the establishment of prognostic signatures based on ubiquitination-related genes (UbRGs) and their role in immunotherapy are still lacking in HCC. Methods: We employed datasets from TCGA and GEO for transcriptome differential expression analysis and single-cell RNA sequencing analysis. Applying weighted gene co-expression network analysis, cox regression, lasso, selection and visualization of the most relevant features, and gradient boosting machine, we identified hub UbRGs as a gene signature to develop a prognostic model. We evaluated the predictive utility concerning clinical characteristics as well as its role in the immune landscape and immunotherapy potential. Additionally, western blotting, reverse transcription-quantitative PCR, and immunofluorescence were employed to detect the expression and sub-localization of hub genes. Results: Three hub UbRGs (BOP1, CDC20, and UBE2S) were identified as a gene signature. In particular, the high-risk group exhibited notable characteristics, including higher tumor mutation burden, enrichment in immune-related pathways, up-regulation immune checkpoint, and higher immunity scores. Treatment response to immunotherapy varied based on the expression of PD-1 and CTLA-4. Furthermore, single-cell data analysis revealed heterogeneous expression of hub UbRGs across different cell subtypes, while cytological experiments provided additional confirmation of the high expression of hub UbRGs in HCC. Conclusion: Our study provides valuable insights into the identification of novel ubiquitination-related biomarkers with potential applications for prognosis, immunotherapy prediction, and drug sensitivity in HCC.

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A review of deubiquitinases and thier roles in tumorigenesis and development

Cited by 7 publications

References 124 publications

The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis

The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis

Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

Prognostic and Immune Landscape Analysis of Ubiquitination-related Genes in Hepatocellular Carcinoma: Based on Bulk and Single-cell RNA Sequencing Data

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