The role of the deubiquitinating enzyme DUB3/USP17 in cancer: a narrative review

Yang, Guangfei; Zhang, Xin; Su, Yi-Ge; Zhao, Ren; Wang, Yan-Yang

doi:10.1186/s12935-021-02160-y

Cited by 13 publications

(8 citation statements)

References 87 publications

(89 reference statements)

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“…The USP family constitutes the largest family of DUBs, with about 58 members; however, this number grows significantly when accounting for alternative isoforms, especially the highly similar USP17-likes gene [ 4 , 5 , 6 , 7 ]. USPs share a structurally homologous catalytic domain (CD) but are diverse in their composition of accessory domains that are critical for protein-protein interactions and activity regulation via inter- and intramolecular allosteric mechanisms [ 3 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates

Zheng

Chen

Guo

et al. 2023

Cells

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Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a range of other substrates, including proteins from both the cytoplasm and nucleus. USP16 is phosphorylated when cells enter mitosis and dephosphorylated during the metaphase/anaphase transition. While much of USP16 is localized in the cytoplasm, separating the enzyme from its substrates is considered an important regulatory mechanism. Some of the functions that USP16 has been linked to include DNA damage repair, immune disease, tumorigenesis, protein synthesis, coronary artery health, and male infertility. The strong connection to immune response and the fact that multiple oncogene products are substrates of USP16 suggests that USP16 may be a potential therapeutic target for the treatment of certain human diseases.

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Section: Introductionmentioning

confidence: 99%

The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates

Zheng

Chen

Guo

et al. 2023

Cells

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“…USP7 is one of the most extensively studied USPs, and quite a number of anti‐cancer compounds targeting USP7 have been developed 33 . Moreover, USP8, USP9X, USP17, USP20, USP28 and UCHL5 have attracted increasing attention due to their potential roles in tumorigenesis and cancer therapy 34–40 . At the tested concentration of 10 µM, COH29 showed no significant inhibition effect on the enzymatic activities of deubiquitinases USP7, USP9X, USP17, and USP20.…”

Section: Resultsmentioning

confidence: 99%

“…33 Moreover, USP8, USP9X, USP17, USP20, USP28 and UCHL5 have attracted increasing attention due to their potential roles in tumorigenesis and cancer therapy. [34][35][36][37][38][39][40] At the tested concentration of 10 µM, COH29 showed no significant inhibition effect on the enzymatic activities of deubiquitinases USP7, USP9X, USP17, and USP20. Meanwhile, the compound exhibited weak inhibition activities against USP28 and UCHL5 (Figure 2D).…”

Section: Inhibition Selectivity Of Coh29 On Usp2 Over Other Deubiquit...mentioning

confidence: 92%

Ribonucleotide reductase holoenzyme inhibitor COH29 interacts with deubiquitinase ubiquitin‐specific protease 2 and downregulates its substrate protein cyclin D1

et al. 2022

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USP2 contributes to the quality control of multiple oncogenic proteins including cyclin D1, Mdm2, Aurora‐A, etc., and it is a potential target for anti‐cancer drug development. However, currently only a few inhibitors with moderate inhibition activities against USP2 have been discovered. USP2‐targeted active compounds with either new scaffolds or enhanced activities are in need. Here in this study, Ub‐AMC hydrolysis assay‐based screening against ~4000 commercially available drugs and drug candidates was performed to identify USP2‐targeted inhibitors. COH29, which was originally developed as an anti‐cancer agent by blocking the function of human ribonucleotide reductase (RNR, IC50 = 16 µM), was found to exhibit an inhibition activity against USP2 with the IC50 value at 2.02 ± 0.16 µM. The following conducted biophysical and biochemical experiments demonstrated that COH29 could specifically interact with USP2 and inhibit its enzymatic activity in a noncompetitive inhibition mode (Ki = 1.73 ± 0.14 µM). Since COH29 shows similar inhibitory potencies against RNR (RRM2) and USP2, USP2 inhibition‐dependent cellular consequences of COH29 are expected. The results of cellular assays confirmed that the application of COH29 could downregulate the level of cyclin D1 by enhancing its degradation via ubiquitin‐proteasome system (UPS), and the modulation effect of COH29 on cyclin D1 is independent of RRM2. Since cyclin D1 acts as an oncogenic driver in human cancer, our findings suggest that USP2 might be a promising therapeutic target for cyclin D1‐addicted cancers, and COH29 could serve as a starting compound for high selectivity inhibitor development against USP2.

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“…Furthermore, results from the protein-coding network exhibited a high representation of USP17 gene family. USP17 subfamily genes encoding deubiquitinating enzymes were identified as immediate early genes that can be rapidly induced in response to cytokine stimulation in mice and humans [ 31 ]. Specifically, USP17 has been shown to regulate inflammation, cell motility, Th17 cell development, and oncogenesis [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

A Case Series Exploration of Multi-Regional Expression Heterogeneity in Triple-Negative Breast Cancer Patients

Kaur

Wylie

et al. 2022

IJMS

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Extensive intratumoral heterogeneity (ITH) is believed to contribute to therapeutic failure and tumor recurrence, as treatment-resistant cell clones can survive and expand. However, little is known about ITH in triple-negative breast cancer (TNBC) because of the limited number of single-cell sequencing studies on TNBC. In this study, we explored ITH in TNBC by evaluating gene expression-derived and imaging-derived multi-region differences within the same tumor. We obtained tissue specimens from 10 TNBC patients and conducted RNA sequencing analysis of 2–4 regions per tumor. We developed a novel analysis framework to dissect and characterize different types of variability: between-patients (inter-tumoral heterogeneity), between-patients across regions (inter-tumoral and region heterogeneity), and within-patient, between-regions (regional intratumoral heterogeneity). We performed a Bayesian changepoint analysis to assess and classify regional variability as low (convergent) versus high (divergent) within each patient feature (TNBC and PAM50 subtypes, immune, stroma, tumor counts and tumor infiltrating lymphocytes). Gene expression signatures were categorized into three types of variability: between-patients (108 genes), between-patients across regions (183 genes), and within-patients, between-regions (778 genes). Based on the between-patient gene signature, we identified two distinct patient clusters that differed in menopausal status. Significant intratumoral divergence was observed for PAM50 classification, tumor cell counts, and tumor-infiltrating T cell abundance. Other features examined showed a representation of both divergent and convergent results. Lymph node stage was significantly associated with divergent tumors. Our results show extensive intertumoral heterogeneity and regional ITH in gene expression and image-derived features in TNBC. Our findings also raise concerns regarding gene expression based TNBC subtyping. Future studies are warranted to elucidate the role of regional heterogeneity in TNBC as a driver of treatment resistance.

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The role of the deubiquitinating enzyme DUB3/USP17 in cancer: a narrative review

Cited by 13 publications

References 87 publications

The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates

The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates

Ribonucleotide reductase holoenzyme inhibitor COH29 interacts with deubiquitinase ubiquitin‐specific protease 2 and downregulates its substrate protein cyclin D1

A Case Series Exploration of Multi-Regional Expression Heterogeneity in Triple-Negative Breast Cancer Patients

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