Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis

Su, Dongxue; Ma, Shuai; Lin, Shuo; Wang, Yue; Wang, Yuejiao; Cao, Cheng; Liu, Beibei; Yang, Chao; Wang, Liyong; Tian, Shanshan; Ding, Xiang; Liu, Xinhua; Yu, Na; Song, Nan; Liu, Ling; Yang, Shangda; Zhang, Qi; Yang, Fuquan; Zhang, Kai; Shi, Lei

doi:10.1172/jci120518

Cited by 93 publications

(80 citation statements)

References 83 publications

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“…Ubiquitin-specific protease 7 (USP7), also named as herpesvirus-associated ubiquitin-specific protease (HAUSP) is one of the most investigated DUBs and has been associated with the initiation and progression of various cancers (Masuya et al, 2006;Su et al, 2018). USP7 has a broad range of substrates, such as the tumor suppressors p53 and PTEN (Phosphatase and tensin homolog) (Song et al, 2008) and the transcription factor FOXO4 (Forkhead box protein O4) (van der Horst et al, 2006), most of which are related to tumor suppression, DNA repair, and immune response (Pozhidaeva and Bezsonova, 2019).…”

Section: Introductionmentioning

confidence: 99%

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitinproteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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“…However, the protein that guarantees the stability of EZH2 has not been identified until now. USP7 has been reported to stabilize a number of proteins, thereby playing a role in multiple cellular processes (24, 25). Given our finding that USP7 is physically associated with the PRC2 complex, it is reasonable that USP7 would stabilize EZH2 through its deubiquitinase activity.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we recently reported that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating several key cell cycle regulators such as cyclin A2 (24). USP7 was also found to stabilize mediator of DNA damage checkpoint protein 1 (MDC1), which promoted cervical cancer cell survival and conferred cellular resistance to genotoxic insults (25). Although elevated USP7 expression was recently reported as a distinct gene signature of malignant melanoma (26), its specific contribution to melanoma progression is largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis

Wang

Hou³

et al. 2019

Preprint

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Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in melanoma cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation.Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives melanoma cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during melanoma progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of melanoma patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for melanoma.

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“…53 Moreover, USP7 contributes to cervical carcinogenesis and its expression levels are associated with worse survival rates for patients with cervical cancer. 53 In summary, the findings presented here suggest that USP9X is a novel binding partner of BRCA1 and stabilizes BRCA1. Moreover, knockdown of USP9X enhances the sensitivity of human cancer cells to PARP inhibitor Olaparib and MMS.…”

Section: F I G U R E 3 Usp9x Interacts With Brca1 a And B Hek293tmentioning

confidence: 99%

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

Zhang

et al. 2019

Cancer Medicine

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BRCA1, a multifunctional protein with an important role in DNA double‐strand break repair by homologous recombination (HR), is subjected to ubiquitin‐dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin‐specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small‐molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild‐type USP9X, but not its deubiquitinase activity‐defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half‐life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X‐depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA‐damaging agents.

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Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis

Cited by 93 publications

References 83 publications

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

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