Ubiquitin-specific protease 7 is a drug-able target that promotes hepatocellular carcinoma and chemoresistance

Zhang, Wei; Zhang, Jingxin; Xu, Chenzhou; Zhang, Shiqing; Bian, Saiyan; Jiang, Feng; Ni, Wenkai; Qu, Lei; Lu, Cuihua; Ni, Runzhou; Fan, Yihui; Xiao, Mingbing; Liu, Jinxia

doi:10.1186/s12935-020-1109-2

Cited by 29 publications

(21 citation statements)

References 39 publications

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“…Enthusiasm for this approach is demonstrated by the dozens of small molecule USP7 inhibitors developed in the past few years. While human trials of USP7 inhibitors have yet to be conducted, many of these compounds have been found to inhibit cancer cell growth in vitro , as well as in animal xenograft models ( Fan et al, 2013 ; Agathanggelou et al, 2017 ; Turnbull et al, 2017 ; Peng et al, 2019 ; Zhang et al, 2020 ). The molecular basis of the interaction between several inhibitors and USP7 has been determined, revealing that these small molecules largely target the USP7 catalytic domain [ Figure 4 and Table 2 ; for a recent and extensive review, see Li and Liu (2020) ].…”

Section: Usp7: Links With Cancermentioning

confidence: 99%

USP7 Is a Master Regulator of Genome Stability

Valles

Bezsonova

Woodgate

et al. 2020

Front. Cell Dev. Biol.

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Genetic alterations, including DNA mutations and chromosomal abnormalities, are primary drivers of tumor formation and cancer progression. These alterations can endow cells with a selective growth advantage, enabling cancers to evade cell death, proliferation limits, and immune checkpoints, to metastasize throughout the body. Genetic alterations occur due to failures of the genome stability pathways. In many cancers, the rate of alteration is further accelerated by the deregulation of these processes. The deubiquitinating enzyme ubiquitin specific protease 7 (USP7) has recently emerged as a key regulator of ubiquitination in the genome stability pathways. USP7 is also deregulated in many cancer types, where deviances in USP7 protein levels are correlated with cancer progression. In this work, we review the increasingly evident role of USP7 in maintaining genome stability, the links between USP7 deregulation and cancer progression, as well as the rationale of targeting USP7 in cancer therapy.

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Section: Usp7: Links With Cancermentioning

confidence: 99%

USP7 Is a Master Regulator of Genome Stability

Valles

Bezsonova

Woodgate

et al. 2020

Front. Cell Dev. Biol.

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“…Of them, through deubiquitinating a wide range of substrates, USPs family members are involved in various physiological and pathological processes. Our previous study has suggested USP7 as a drug-able target that promoted chemoresistance of HCC (8). Recently, increasing studies indicate that USPs are implicated in the progression of HCC.…”

Section: Introductionmentioning

confidence: 98%

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

Bian

Zhu

et al. 2021

Front. Oncol.

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PurposeUbiquitin-specific proteases (USPs), as a sub-family of deubiquitinating enzymes (DUBs), are responsible for the elimination of ubiquitin-triggered modification. USPs are recently correlated with various malignancies. However, the expression features and clinical significance of USPs have not been systematically investigated in hepatocellular carcinoma (HCC).MethodsGenomic alterations and expression profiles of USPs were investigated in CbioPortal and The Cancer Genome Atlas (TCGA) Liver hepatocellular carcinoma (LIHC) dataset. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were conducted to establish a risk signature for HCC prognosis in TCGA LIHC cohort. Subsequently, Kaplan-Meier analysis, receiver operating characteristic (ROC) curves and univariate/multivariate analyses were performed to evaluate the prognostic significance of the risk signature in TCGA LIHC and international cancer genome consortium (ICGC) cohorts. Furthermore, we explored the alterations of the signature genes during hepatocarcinogenesis and HCC progression in GSE89377. In addition, the expression feature of USP39 was further explored in HCC tissues by performing western blotting and immunohistochemistry.ResultsGenomic alterations and overexpression of USPs were observed in HCC tissues. The consensus analysis indicated that the USPs-overexpressed sub-Cluster was correlated with aggressive characteristics and poor prognosis. Cox regression with LASSO algorithm identified a risk signature formed by eight USPs for HCC prognosis. High-risk group stratified by the signature score was correlated with advanced tumor stage and poor survival HCC patients in TCGA LIHC cohort. In addition, the 8-USPs based signature could also robustly predict overall survival of HCC patients in ICGC(LIRI-JP) cohort. Furthermore, gene sets enrichment analysis (GSEA) showed that the high-risk score was associated with tumor-related pathways. According to the observation in GSE89377, USP39 expression was dynamically increased with hepatocarcinogenesis and HCC progression. The overexpression of USP39 was further determined in a local HCC cohort and correlated with poor prognosis. The co-concurrence analysis suggested that USP39 might promote HCC by regulating cell-cycle- and proliferation- related genes.ConclusionThe current study provided a USPs-based signature, highlighting its robust prognostic significance and targeted value for HCC treatment.

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“…For example, USP7 promotes intrinsic apoptosis through p53, SUV39H1, and PLK1 and suppresses intrinsic apoptosis through MDM2 and Maf and suppresses the ER stress response. In addition, USP7 promotes extrinsic apoptosis by promoting RIPK1 activity and ferroptosis by suppressing SCL7A11 expression (Figure 3a) [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. BAP1 provides another example of the complex regulation of RCD through diverse mediators.…”

Section: Dubs Regulating Diverse Rcdmentioning

confidence: 99%

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

Lee

Kim

Hwang

et al. 2021

IJMS

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The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.

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Ubiquitin-specific protease 7 is a drug-able target that promotes hepatocellular carcinoma and chemoresistance

Cited by 29 publications

References 39 publications

USP7 Is a Master Regulator of Genome Stability

USP7 Is a Master Regulator of Genome Stability

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

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

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