Gene Summary

Gene:USP7; ubiquitin specific peptidase 7
Aliases: TEF1, HAUSP
Summary:The protein encoded by this gene belongs to the peptidase C19 family, which includes ubiquitinyl hydrolases. This protein deubiquitinates target proteins such as p53 (a tumor suppressor protein) and WASH (essential for endosomal protein recycling), and regulates their activities by counteracting the opposing ubiquitin ligase activity of proteins such as HDM2 and TRIM27, involved in the respective process. Mutations in this gene have been implicated in a neurodevelopmental disorder. [provided by RefSeq, Mar 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ubiquitin carboxyl-terminal hydrolase 7
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (24)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: USP7 (cancer-related)

Morra F, Merolla F, Criscuolo D, et al.
CCDC6 and USP7 expression levels suggest novel treatment options in high-grade urothelial bladder cancer.
J Exp Clin Cancer Res. 2019; 38(1):90 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The muscle invasive form of urothelial bladder cancer (UBC) is a deadly disease. Currently, the therapeutic approach of UBC is mostly based on surgery and standard chemotherapy. Biomarkers to establish appropriate drugs usage are missing. Deficiency of the tumor suppressor CCDC6 determines PARP-inhibitor sensitivity. The CCDC6 levels are modulated by the deubiquitinase USP7. In this work we scored CCDC6 and USP7 expression levels in primary UBC and we evaluated the expression levels of CCDC6 in correlation with the effects of the PARP-inhibitors combined with the USP7 inhibitor, P5091, in vitro. Since PARP-inhibitors could be enhanced by conventional chemotherapy or DNA damage inducers, we tested the new agent RRx-001, able to induce DNA damage, to prove the benefit of combined treatments in bladder cancer cells.
METHODS: The J82, T24, 5637 and KU-19-19 bladder cancer cells were exposed to USP7 inhibitor P5091 in presence of cycloheximide to analyse the CCDC6 stability. Upon the CCDC6 degradation induced by P5091, the cells sensitivity to PARP-inhibitor was evaluated by cell viability assays. The ability of the DNA damage inducer RRx-001 to modulate CCDC6 protein levels and H2AX phosphorylation was detected at immunoblot. The combination of USP7 inhibitor plus RRx-001 enhanced the PARP-inhibitor sensitivity, as evaluated by cell viability assays. The results of the scores and correlation of CCDC6 and USP7 expression levels obtained by UBC primary biopsies staining were used to cluster patients by a K-mean cluster analysis.
RESULTS: P5091 determining CCDC6 degradation promoted bladder cancer cells sensitivity to PARP-inhibitor drugs. RRx-001, by inducing DNA damage, enhanced the effects of the combined treatment. The immunohistochemical staining of both CCDC6 and USP7 proteins allowed to cluster the high grade (G3) UBC patients, on the basis of CCDC6 expression levels.
CONCLUSIONS: In high grade UBC the identification of two clusters of patients based on CCDC6 and USP7 expession can possibly indicate the use of PARP-inhibitor drugs, in combination with USP7 inhibitor in addition to the DNA damage inducer RRx-001, that also acts as an immunomodulatory agent, offering novel therapeutic strategy for personalized medicine in bladder cancer patients.

Zhang H, Deng T, Ge S, et al.
Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7.
Oncogene. 2019; 38(15):2844-2859 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC), the major form of liver cancer, has shown increasing incidence and poor prognosis. Adipose tissue is known to function in energy storage and metabolism regulation by the secretion of adipokines. Circular RNAs (circRNAs), a novel type of noncoding RNA, have recently been recognized as key factors in tumor development, but the role of exosome circRNAs derived from adipose tissues has not been defined yet. Here, adipose-secreted circRNAs were found to regulate deubiquitination in HCC, thus facilitating cell growth. It was observed that exosome circ-deubiquitination (circ-DB) is upregulated in HCC patients with higher body fat ratios. Moreover, in vitro and in vivo studies showed that exo-circ-DB promotes HCC growth and reduces DNA damage via the suppression of miR-34a and the activation of deubiquitination-related USP7. Finally, the results showed that the effects of adipose exosomes on HCC cells can be reversed by knockdown of circ-DB. These results indicate that exosome circRNAs secreted from adipocytes promote tumor growth and reduce DNA damage by suppressing miR-34a and activating the USP7/Cyclin A2 signaling pathway.

Zeng Q, Li Z, Zhao X, et al.
Ubiquitin‑specific protease 7 promotes osteosarcoma cell metastasis by inducing epithelial‑mesenchymal transition.
Oncol Rep. 2019; 41(1):543-551 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary malignant bone tumour among adolescents and young adults; however, its molecular pathogenesis has not been completely elucidated. Ubiquitin‑specific protease 7 (USP7), a member of the deubiquitinating enzyme family, plays a role in the malignancy process of various cancer types by targeting the key oncoprotein; however, its biological function and mechanism in OS have not been elucidated. The present study demonstrated that USP7 expression in OS tumour tissues was markedly higher than that in the paired surrounding tissues, and high USP7 expression was positively correlated with the TNM stage and metastasis in patients with OS. Next, biological function assays demonstrated that USP7 knockdown markedly inhibited OS cell migration and invasion, whereas USP7 overexpression enhanced it. Notably, USP7 can directly bind with β‑catenin to activate the Wnt/β‑catenin signalling pathway and induce epithelial‑mesenchymal transition (EMT) of OS cells. Overall, USP7 overexpression could promote OS cell metastasis by activating the Wnt/β‑catenin signalling pathway by inducing EMT, suggesting that USP7 is a potential therapeutic target for OS.

Wei R, Wu Y
Modification effect of fenofibrate therapy, a longitudinal epigenomic-wide methylation study of triglycerides levels in the GOLDN study.
BMC Genet. 2018; 19(Suppl 1):75 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Identification of interactions between epigenetic factors and treatments might lead to personalized intervention of diseases. This paper aims to examine the modification effect of fenofibrate therapy on the association of methylation levels and fasting blood triglycerides (TG), and the related biological pathways among methylation sites.
RESULTS: Mixed-effects models were employed to assess pre- and posttreatment associations and drug modification effects simultaneously. Five cytosine-phosphate-guanine (CpG) sites were found to be associated with TG levels before and after the fenofibrate therapy: cg00574958, cg17058475, and cg01082498 on CPT1A gene, chromosome 11; cg03725309 on SARS, chromosome 1; and cg06500161 on ABCG1, chromosome 21. In addition, fenofibrate therapy modified the methylation levels on the following 4 CpG sites: cg20015535 (gene EGLN1, chromosome 1); cg24870738 (gene RNF220, chromosome 1); cg06891775 (gene LOC283050, chromosome 10); and cg00607630 (gene USP7, chromosome 16). Further, gene set enrichment analysis (GSEA) identified cancer- and metabolism-related pathways that were associated with TG-related CpG sites.
CONCLUSIONS: We identified modification effects of fenofibrate on the associations between blood TG levels and several CpG sites. Pathway enrichment analysis indicated the alternations in some metabolism and cancer-related pathways. Our findings have important implications for future research in pharmacoepigenetics and personalized medicine.

Callegari K, Maegawa S, Bravo-Alegria J, Gopalakrishnan V
Pharmacological inhibition of LSD1 activity blocks REST-dependent medulloblastoma cell migration.
Cell Commun Signal. 2018; 16(1):60 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor in children. Current problems in the clinic include metastasis, recurrence, and treatment-related sequelae that highlight the need for targeted therapies. Epigenetic perturbations are an established hallmark of human MB and expression of Lysine Specific Demethylase 1 (LSD1) is elevated in MBs compared to normal tissue, suggesting that LSD1 inhibitors may have efficacy against human MB tumors.
METHODS: Expression of LSD1 was examined across a publicly-available database and correlated with patient outcomes. Sonic Hedgehog (SHH) MB samples were clustered based on expression of LSD1 and LSD1-associated RE-1 silencing transcription factor (REST) target genes as well as genes involved in metastasis. Resulting clusters were examined for patient outcomes associated with LSD1 and REST expression. Human SHH MB cell lines were transduced with a REST-transgene to create isogenic cell pairs. In vitro viability and cell migration assays were used to examine the effect of LSD1 knockdown or inhibition on these parameters.
RESULTS: We demonstrate that subsets of SHH MB tumors have elevated LSD1 expression coincident with increased expression of its deubiquitylase, USP7, and REST. Patients with co-elevation of USP7, REST, and LSD1 have poorer outcomes compared to those with lower expression of these genes. In SHH MB cell lines, REST elevation increased cell growth and LSD1 protein levels. Surprisingly, while genetic loss of LSD1 reduced cell viability, pharmacological targeting of its activity using LSD1 inhibitors did not affect cell viability. However, a reduction in REST-dependent cell migration was seen in wound healing, suggesting that REST-LSD1 interaction regulates cell migration. Ingenuity pathway analyses validated these findings and identified Hypoxia Inducible Factor 1 alpha (HIF1A) as a potential target. In line with this, ectopic expression of HIF1A rescued the loss of migration seen following LSD1 inhibition.
CONCLUSIONS: A subset of SHH patients display increased levels of LSD1 and REST, which is associated with poor outcomes. REST elevation in MB in conjunction with elevated LSD1 promotes MB cell migration. LSD1 inhibition blocks REST-dependent cell migration of MB cells in a HIF1A-dependent manner.

Hu T, Zhang J, Sha B, et al.
Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA-mediated apoptosis.
Mol Carcinog. 2019; 58(1):42-54 [PubMed] Related Publications
Increasing evidence suggests that deubiquitinase USP7 participates in tumor progression by various mechanisms and serves as a potential therapeutic target. However, its expression and role in esophageal cancer remains elusive; the anti-cancer effect by targeting USP7 still needs to be investigated. Here, we reported that USP7 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent tissues, implying that USP7 was an attractive anticancer target of ESCC. Pharmaceutical or genetic inactivation of USP7 inhibited esophageal cancer cells growth in vitro and in vivo and induced apoptosis. Mechanistically, inhibition of USP7 accumulated poly-ubiquitinated proteins, activated endoplasmic reticulum stress, and increased expression of ATF4, which transcriptionally upregulated expression of NOXA and induced NOXA-mediated apoptosis. These results provide an evidence for clinical investigation of USP7 inhibitors for the treatment of ESCC.

Yao Y, Zhang Y, Shi M, et al.
Blockade of deubiquitinase USP7 overcomes bortezomib resistance by suppressing NF-κB signaling pathway in multiple myeloma.
J Leukoc Biol. 2018; 104(6):1105-1115 [PubMed] Related Publications
The treatment of multiple myeloma (MM) with bortezomib (BTZ) is promising; however, the emergence of resistance is challenging in the clinical treatment. Thus, a novel targeted treatment or exploring the mechanism underlying BTZ resistance is an urgent requisite. The current data showed that high expression of USP7 in myeloma was a predictor of short overall survival and poor outcome. USP7 knockout significantly suppressed the colony formation, inhibited the proliferation of BTZ-resistant MM cells even in the presence of growth factors, and overcame BTZ resistance. The knockout markedly inhibited the tumor growth and prolonged the survival of mice bearing BTZ-resistant MM cells. Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing ΙκΒα and blocking the NF-κB pathway. Not surprisingly, when IκBα was knocked down by siRNA transfection, the MM cells restored the BTZ resistance. Importantly, usage of USP7 inhibitors also suppressed the activation of NF-κB and combination with BTZ triggered the synergistic antitumor activity in BTZ-resistant MM cells. Taken together, this study provides the rationale for clinical protocols evaluating USP7 inhibition, alone and in combination with BTZ, to overcome BTZ resistance and improve the patient outcome in MM.

Beck A, Trippel F, Wagner A, et al.
Overexpression of
Clin Epigenetics. 2018; 10:27 [PubMed] Free Access to Full Article Related Publications
Background: Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification.
Results: We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs)
Conclusion: These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that

Biswas K, Philip S, Yadav A, et al.
BRE/BRCC45 regulates CDC25A stability by recruiting USP7 in response to DNA damage.
Nat Commun. 2018; 9(1):537 [PubMed] Free Access to Full Article Related Publications
BRCA2 is essential for maintaining genomic integrity. BRCA2-deficient primary cells are either not viable or exhibit severe proliferation defects. Yet, BRCA2 deficiency contributes to tumorigenesis. It is believed that mutations in genes such as TRP53 allow BRCA2 heterozygous cells to overcome growth arrest when they undergo loss of heterozygosity. Here, we report the use of an insertional mutagenesis screen to identify a role for BRE (Brain and Reproductive organ Expressed, also known as BRCC45), known to be a part of the BRCA1-DNA damage sensing complex, in the survival of BRCA2-deficient mouse ES cells. Cell viability by BRE overexpression is mediated by deregulation of CDC25A phosphatase, a key cell cycle regulator and an oncogene. We show that BRE facilitates deubiquitylation of CDC25A by recruiting ubiquitin-specific-processing protease 7 (USP7) in the presence of DNA damage. Additionally, we uncovered the role of CDC25A in BRCA-mediated tumorigenesis, which can have implications in cancer treatment.

Novellasdemunt L, Foglizzo V, Cuadrado L, et al.
USP7 Is a Tumor-Specific WNT Activator for APC-Mutated Colorectal Cancer by Mediating β-Catenin Deubiquitination.
Cell Rep. 2017; 21(3):612-627 [PubMed] Free Access to Full Article Related Publications
The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRCs), resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of the APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex. USP7 depletion in APC-mutated CRC inhibits Wnt activation by restoring β-catenin ubiquitination, drives differentiation, and suppresses xenograft tumor growth. Finally, the Wnt-activating role of USP7 is specific to APC mutations; thus, it can be used as a tumor-specific therapeutic target for most CRCs.

Turnbull AP, Ioannidis S, Krajewski WW, et al.
Molecular basis of USP7 inhibition by selective small-molecule inhibitors.
Nature. 2017; 550(7677):481-486 [PubMed] Free Access to Full Article Related Publications
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.

Sho S, Court CM, Winograd P, et al.
A prognostic mutation panel for predicting cancer recurrence in stages II and III colorectal cancer.
J Surg Oncol. 2017; 116(8):996-1004 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Approximately 20-40% of stage II/III colorectal cancer (CRC) patients develop relapse. Clinicopathological factors alone are limited in detecting these patients, resulting in potential under/over-treatment. We sought to identify a prognostic tumor mutational profile that could predict CRC recurrence.
METHODS: Whole-exome sequencing data were obtained for 207 patients with stage II/III CRC from The Cancer Genome Atlas. Mutational landscape in relapse-free versus relapsed cohort was compared using Fisher's exact test, followed by multivariate Cox regression to identify genes associated with cancer recurrence. Bootstrap-validation was used to examine internal/external validity.
RESULTS: We identified five prognostic genes (APAF1, DIAPH2, NTNG1, USP7, and VAV2), which were combined to form a prognostic mutation panel. Patients with ≥1 mutation(s) within this five-gene panel had worse prognosis (3-yr relapse-free survival [RFS]: 53.0%), compared to patients with no mutation (3-yr RFS: 84.3%). In multivariate analysis, the five-gene panel remained prognostic for cancer recurrence independent of stage and high-risk features (hazard ratio 3.63, 95%CI [1.93-6.83], P < 0.0001). Furthermore, its prognostic accuracy was superior to the American Joint Commission on Cancer classification (concordance-index: 0.70 vs 0.54).
CONCLUSIONS: Our proposed mutation panel identifies CRC patients at high-risk for recurrence, which may help guide adjuvant therapy and post-operative surveillance protocols.

Macedo GS, Vieira IA, Vianna FSL, et al.
p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers.
Fam Cancer. 2018; 17(2):269-274 [PubMed] Related Publications
Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186). Cancer-affected carriers had been diagnosed either with adrenocortical carcinoma (ACC, n = 29) or breast cancer (BC, n = 43). Allelic discrimation using TaqMan assay was used for genotyping MDM2 SNP 309 (rs2279744) as well as MDM4 (rs1563828) and USP7 (rs1529916) polymorphisms. We found significantly higher MDM2 SNP 309 GG genotype and G allele frequencies in the LFS cohort than in controls. Furthermore, median age at first diagnosis was earlier in MDM2 SNP309 GG carriers when compared to other genotypes for both cancers (ACC: age 1 vs. 2 years; BC: age 35 vs. 43 years, respectively), although not statistically different. The allelic and genotypic frequencies for all SNPs did not differ between cancer affected and unaffected carriers, neither between patients with ACC or BC. In conclusion, our results suggest that MDM2 SNP 309 may contribute to the LFL phenotype and also to an earlier age at diagnosis of ACC and BC cancer in carriers of the R337H founder mutation.

Agathanggelou A, Smith E, Davies NJ, et al.
USP7 inhibition alters homologous recombination repair and targets CLL cells independently of ATM/p53 functional status.
Blood. 2017; 130(2):156-166 [PubMed] Related Publications
The role of deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whereas previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we recently showed that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome. We demonstrate that USP7 is upregulated in CLL cells, and its loss or inhibition disrupts homologous recombination repair (HRR). Consequently, USP7 inhibition induces significant tumor-cell killing independently of ATM and p53 through the accumulation of genotoxic levels of DNA damage. Moreover, USP7 inhibition sensitized p53-defective, chemotherapy-resistant CLL cells to clinically achievable doses of HRR-inducing chemotherapeutic agents in vitro and in vivo in a murine xenograft model. Together, these results identify USP7 as a promising therapeutic target for the treatment of hematological malignancies with DDR defects, where ATM/p53-dependent apoptosis is compromised.

Carrà G, Panuzzo C, Torti D, et al.
Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones.
Oncotarget. 2017; 8(22):35508-35522 [PubMed] Free Access to Full Article Related Publications
Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL.

An T, Gong Y, Li X, et al.
USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth.
Biochem Pharmacol. 2017; 131:29-39 [PubMed] Related Publications
Aberrant activation of Wnt/β-catenin signaling is closely associated with the development of various human cancers, especially colorectal cancers (CRC). The ubiquitin proteasome system (UPS) is essential in the regulation of Wnt signaling and inhibitors targeting the UPS could have great potential in CRC therapy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, plays a significant role in neoplastic diseases due to its well-known function of regulating the MDM2-p53 complex. Inspired by our recent study identifying the positive role of USP7 in the Wnt signaling, we report here that USP7 is overexpressed in colorectal carcinoma cell lines and tissues, which is closely related with the poor prognosis. USP7 knockdown inhibits the proliferation of CRC cells with different p53 status, and USP7 inhibition by its inhibitor P5091 attenuates the activity of Wnt signaling via enhanced ubiquitination and the subsequent degradation of β-catenin. In vitro, P5091 inhibited the proliferation and induced apoptosis of CRC cells. P5091 also suppressed in vivo tumor growth in the HCT116 xenograft mouse model, which is consistently associated with reduced expression of β-catenin and Wnt target genes. In conclusion, our preclinical study indicated that USP7 could be a potential drug target and its inhibitor P5091 deserves further development as anticancer agent for Wnt hyper-activated CRC therapy.

Nihira NT, Ogura K, Shimizu K, et al.
Acetylation-dependent regulation of MDM2 E3 ligase activity dictates its oncogenic function.
Sci Signal. 2017; 10(466) [PubMed] Free Access to Full Article Related Publications
Abnormal activation of the oncogenic E3 ubiquitin ligase murine double minute 2 (MDM2) is frequently observed in human cancers. By ubiquitinating the tumor suppressor p53 protein, which leads to its proteasome-mediated destruction, MDM2 limits the tumor-suppressing activity of p53. On the other hand, by ubiquitinating itself, MDM2 targets itself for destruction and promotes the p53 tumor suppressor pathway, a process that can be antagonized by the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP). We investigated the regulation of MDM2 substrate specificity and found that acetyltransferase p300-mediated acetylation and stabilization of MDM2 are molecular switches that block self-ubiquitination, thereby shifting its E3 ligase activity toward p53. In vitro and in cancer cell lines, p300-mediated acetylation of MDM2 on Lys

Richter-Pechańska P, Kunz JB, Hof J, et al.
Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia.
Blood Cancer J. 2017; 7(2):e523 [PubMed] Free Access to Full Article Related Publications
In the search for genes that define critical steps of relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and can serve as prognostic markers, we performed targeted sequencing of 313 leukemia-related genes in 214 patients: 67 samples collected at the time of relapse and 147 at initial diagnosis. As relapse-specific genetic events, we identified activating mutations in NT5C2 (P=0.0001, Fisher's exact test), inactivation of TP53 (P=0.0007, Fisher's exact test) and duplication of chr17:q11.2-24.3 (P=0.0068, Fisher's exact test) in 32/67 of T-ALL relapse samples. Alterations of TP53 were frequently homozygous events, which significantly correlated with higher rates of copy number alterations in other genes compared with wild-type TP53 (P=0.0004, Mann-Whitney's test). We subsequently focused on mutations with prognostic impact and identified genes governing DNA integrity (TP53, n=8; USP7, n=4; MSH6, n=4), having key roles in the RAS signaling pathway (KRAS, NRAS, n=8), as well as IL7R (n=4) and CNOT3 (n=4) to be exclusively mutated in fatal relapses. These markers recognize 24/49 patients with a second event. In 17 of these patients with mostly refractory relapse and dire need for efficient treatment, we identified candidate targets for personalized therapy with p53 reactivating compounds, MEK inhibitors or JAK/STAT-inhibitors that may be incorporated in future treatment strategies.

Zhan M, Sun X, Liu J, et al.
Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway.
Biochem Biophys Res Commun. 2017; 484(2):429-434 [PubMed] Related Publications
The ubiquitin-specific protease Usp7 plays roles in multiple cellular processes through deubiquitinating and stabilizing numerous substrates, including P53, Pten and Gli. Aberrant Usp7 activity has been implicated in many disorders and tumorigenesis, making it as a potential target for therapeutic intervention. Although it is clear that Usp7 is involved in many types of cancer, its role in regulating medulloblastoma (MB) is still unknown. In this study, we show that knockdown of Usp7 inhibits the proliferation and migration of MB cells, while Usp7 overexpression exerts an opposite effect. Furthermore, we establish Usp7 knockout MB cell line using the CRISPR/Cas9 system and further confirm that Usp7 knockout also blocks MB cell proliferation and metastasis. In addition, we reveal that knockdown of Usp7 compromises Shh pathway activity and decrease Gli protein levels, while P53 level and P53 target gene expression have no obvious changes. Finally, we find that Usp7 inhibitors apparently inhibit MB cell viability and migration. Taken together, our findings suggest that Usp7 is important for MB cell proliferation and metastasis by activating Shh pathway, and is a putative therapeutic target for MBs.

Wu HT, Kuo YC, Hung JJ, et al.
K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression.
Nat Commun. 2016; 7:13644 [PubMed] Free Access to Full Article Related Publications
Intratumoural hypoxia induces HIF-1α and promotes tumour progression, metastasis and treatment resistance. HIF-1α stability is regulated by VHL-E3 ligase-mediated ubiquitin-dependent degradation; however, the hypoxia-regulated deubiquitinase that stabilizes HIF-1α has not been identified. Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF-1α to increase its stability, induce epithelial-mesenchymal transition and promote metastasis. Hypoxia induces K63-linked polyubiquitinated HAUSP at lysine 443 to enhance its functions. Knockdown of HAUSP decreases acetylation of histone 3 lysine 56 (H3K56Ac). K63-polyubiquitinated HAUSP interacts with a ubiquitin receptor CBP to specifically mediate H3K56 acetylation. ChIP-seq analysis of HAUSP and HIF-1α binding reveals two motifs responsive to hypoxia. HectH9 is the E3 ligase for HAUSP and a prognostic marker together with HIF-1α. This report demonstrates that hypoxia-induced K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and causes CBP-mediated H3K56 acetylation on HIF-1α target gene promoters to promote EMT/metastasis, further defining HAUSP as a therapeutic target in hypoxia-induced tumour progression.

Qin D, Wang W, Lei H, et al.
CDDO-Me reveals USP7 as a novel target in ovarian cancer cells.
Oncotarget. 2016; 7(47):77096-77109 [PubMed] Free Access to Full Article Related Publications
Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of α, β-unsaturated ketones. Molecular docking studies showed that CDDO-Me fits well in the ubiquitin carboxyl terminus-binding pocket on USP7. Given that CDDO-Me is known to be effective against ovarian cancer cells, we speculated that CDDO-Me may target USP7 in ovarian cancer cells. We demonstrated that ovarian cancer cells have higher USP7 expression than their normal counterparts. Knockdown of USP7 inhibits the proliferation of ovarian cancer cells both in vitro and in vivo. Using the cellular thermal shift assay and the drug affinity responsive target stability assay, we further demonstrated that CDDO-Me directly binds to USP7 in cells, which leads to the decrease of its substrates such as MDM2, MDMX and UHRF1. CDDO-Me suppresses ovarian cancer tumor growth in an xenograft model. In conclusion, we demonstrate that USP7 is a novel target of ovarian cancer cells; targeting USP7 may contribute to the anti-cancer effect of CDDO-Me. The development of novel USP7 selective compounds based on the CDDO-Me-scaffold warrants further investigation.

Tavana O, Li D, Dai C, et al.
HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma.
Nat Med. 2016; 22(10):1180-1186 [PubMed] Free Access to Full Article Related Publications
The MYCN proto-oncogene is amplified in a number of advanced-stage human tumors, such as neuroblastomas. Similar to other members of the MYC family of oncoproteins, MYCN (also known as N-Myc) is a transcription factor, and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation. Although numerous studies have demonstrated that N-Myc is a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here we have identified ubiquitin-specific protease 7 (USP7; also known as HAUSP) as a regulator of N-Myc function in neuroblastoma. HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc. Conversely, RNA interference (RNAi)-mediated knockdown of USP7 in neuroblastoma cancer cell lines, or genetic ablation of Usp7 in the mouse brain, destabilizes N-Myc, which leads to inhibition of N-Myc function. Notably, HAUSP is more abundant in patients with neuroblastoma who have poorer prognosis, and HAUSP expression substantially correlates with N-Myc transcriptional activity. Furthermore, small-molecule inhibitors of HAUSP's deubiquitinase activity markedly suppress the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models. Taken together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors.

Zhang C, Lu J, Zhang QW, et al.
USP7 promotes cell proliferation through the stabilization of Ki-67 protein in non-small cell lung cancer cells.
Int J Biochem Cell Biol. 2016; 79:209-221 [PubMed] Related Publications
The Ki-67 antigen (Ki-67) is the most reliable immunohistochemical marker for evaluation of cell proliferation in non-small cell lung cancer. However, the mechanisms underlying the regulation of protein levels of Ki-67 in non-small cell lung cancer have remained elusive. In this study, we found that Ki-67 and ubiquitin-specific processing protease 7 (USP7) protein were highly expressed in the nucleus of non-small cell lung cancer cells. Furthermore, statistical analysis uncovered the existence of a strong correlation between Ki-67 and USP7 levels. We could also show that the protein levels of Ki-67 in non-small cell lung cancer cells significantly decreased after treatment with P22077, a selective chemical inhibitor of USP7, while the Ki-67 mRNA levels were unperturbed. Similar results were obtained by knocking down USP7 using short hairpin RNA (shRNA) in lung cancer cells. Interestingly, we noticed that ubiquitination levels of Ki-67 increased dramatically in USP7-silenced cells. The tests in vitro and vivo showed a significant delay in tumor cell growth upon knockdown of USP7. Additionally, drug sensitivity tests indicated that USP7-silenced A549 cells had enhanced sensitivity to paclitaxel and docetaxel, while there was no significant change in sensitivity toward carboplatin and cisplatin. Taken together, these data strongly suggest that the overexpression of USP7 might promote cell proliferation by deubiquitinating Ki-67 protein, thereby maintaining its high levels in the non-small cell lung cancer. Our study also hints potential for the development of deubiquitinase-based therapies, especially those targeting USP7 to improve the condition of patients diagnosed with non-small cell lung cancer.

Malapelle U, Morra F, Ilardi G, et al.
USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs.
Lung Cancer. 2017; 107:41-49 [PubMed] Related Publications
OBJECTIVES: CCDC6 gene product is a tumor-suppressor pro-apoptotic protein, substrate of ATM, involved in DNA damage response and repair. Altered levels of CCDC6 expression are dependent on post-translational modifications, being the de-ubiquitinating enzyme USP7 responsible of the fine tuning of the CCDC6 stability. Thus, our aim was to investigate CCDC6 and USP7 expression levels in Lung-Neuroendocrine Tumors (L-NETs) to verify if they correlate and may be exploited as novel predictive therapeutic markers.
MATERIALS AND METHODS: Tumor tissues from 29 L-NET patients were investigated on tissue microarrays. CCDC6 levels were scored and correlated with immunoreactivity for USP7. Next generation sequencing (NGS) of a homogenous group of Large Cell Neuroendocrine Carcinoma (LCNEC) (N=8) was performed by Ion AmpliSeq NGS platform and the Ion AmpliSeq Cancer Hotspot Panel v2. The inhibition of USP7, using P5091, was assayed in vitro to accelerate CCDC6 turnover in order to sensitize the neuroendocrine cancer cells to PARP-inhibitors, alone or in association with cisplatinum.
RESULTS: The immunostaining of 29 primary L-NETs showed that the intensity of CCDC6 staining correlated with the levels of USP7 expression (p≤0.05). The NGS analysis of 8 LCNEC revealed mutations in the hot spot regions of the p53 gene (in 6 out of 8). Moreover, gene polymorphisms were identified in the druggable STK11, MET and ALK genes. High intensity of p53 immunostaining was reported in the 6 tissues carrying the TP53 mutations. The inhibition of USP7 by P5091 accelerated the degradation of CCDC6 versus control in cycloheximide treated L-NET cells in vitro and sensitized the cells to PARP-inhibitors alone and in combination with cisplatinum.
CONCLUSION: Our data suggest that CCDC6 and USP7 have a predictive value for the clinical usage of USP7 inhibitors in combination with the PARP-inhibitors in L-NET in addition to standard therapy.

Zhang L, Wang H, Tian L, Li H
Expression of USP7 and MARCH7 Is Correlated with Poor Prognosis in Epithelial Ovarian Cancer.
Tohoku J Exp Med. 2016; 239(3):165-75 [PubMed] Related Publications
Epithelial ovarian cancer (EOC) is one of the worst malignancies in females with poor overall survival due to the rapid metastasis and the absence of ideal biomarkers. Ubiquitin-specific protease 7 (USP7), an important deubiquitinating enzyme, was reported to be upregulated in several cancers, including liver, prostate and colon cancers. Membrane associated RING-CH protein 7 (MARCH7) belongs to the member of the E3 ubiquitin ligases. In addition, MARCH7 regulates T cell proliferation and the neuronal development and participates in the membrane trafficking and protein degradation. Importantly, MARCH7 itself is ubiquitinated and acts as a potential substrate of USP7. However, the roles of USP7 and MARCH7 in EOC remain to be investigated. We collected 121 EOC patients and analyzed the expression levels of USP7 and MARCH7 in tumor tissues with immunohistochemical staining. We found that the high expression of the two proteins was correlated with lymph node metastasis in EOC patients. Univariate and multivariate analyses revealed that the patients with high expression of the two proteins showed poorer prognosis compared with other patients. Subsequently, using SKOV3 human ovarian adenocarcinoma cells, we showed that either USP7 or MARCH7 enhanced the proliferation and invasion abilities. Moreover, USP7 could regulate the expression levels of E-cadherin and β-catenin through the MARCH7 signaling pathway. Our findings indicate that USP7 and MARCH7 are involved in the progression of EOC. In conclusion, analyzing the expression of USP7 and MARCH7 has high prognostic value in predicting EOC prognosis.

Wang Q, Ma S, Song N, et al.
Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis.
J Clin Invest. 2016; 126(6):2205-20 [PubMed] Free Access to Full Article Related Publications
The histone demethylase PHF8 has been implicated in multiple pathological disorders, including X-linked mental retardation and tumorigenesis. However, it is not clear how the abundance and function of PHF8 are regulated. Here, we report that PHF8 physically associates with the deubiquitinase USP7. Specifically, we demonstrated that USP7 promotes deubiquitination and stabilization of PHF8, leading to the upregulation of a group of genes, including cyclin A2, that are critical for cell growth and proliferation. The USP7-encoding gene was also transcriptionally regulated by PHF8, via positive feedback. USP7 was overexpressed in breast carcinomas, and the level of expression positively correlated with expression of PHF8 and cyclin A2 and with the histological grade of breast cancer. We showed that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2 and that the interaction between USP7 and PHF8 is augmented during DNA damage. Moreover, USP7-promoted PHF8 stabilization conferred cellular resistance to genotoxic insults and was required for the recruitment of BLM and KU70, which are both essential for DNA double-strand break repair. Our study mechanistically links USP7 to epigenetic regulation and DNA repair. Moreover, these data support the pursuit of USP7 and PHF8 as potential targets for breast cancer intervention, especially in combination with chemo- or radiotherapies.

Srihari S, Singla J, Wong L, Ragan MA
Inferring synthetic lethal interactions from mutual exclusivity of genetic events in cancer.
Biol Direct. 2015; 10:57 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Synthetic lethality (SL) refers to the genetic interaction between two or more genes where only their co-alteration (e.g. by mutations, amplifications or deletions) results in cell death. In recent years, SL has emerged as an attractive therapeutic strategy against cancer: by targeting the SL partners of altered genes in cancer cells, these cells can be selectively killed while sparing the normal cells. Consequently, a number of studies have attempted prediction of SL interactions in human, a majority by extrapolating SL interactions inferred through large-scale screens in model organisms. However, these predicted SL interactions either do not hold in human cells or do not include genes that are (frequently) altered in human cancers, and are therefore not attractive in the context of cancer therapy.
RESULTS: Here, we develop a computational approach to infer SL interactions directly from frequently altered genes in human cancers. It is based on the observation that pairs of genes that are altered in a (significantly) mutually exclusive manner in cancers are likely to constitute lethal combinations. Using genomic copy-number and gene-expression data from four cancers, breast, prostate, ovarian and uterine (total 3980 samples) from The Cancer Genome Atlas, we identify 718 genes that are frequently amplified or upregulated, and are likely to be synthetic lethal with six key DNA-damage response (DDR) genes in these cancers. By comparing with published data on gene essentiality (~16000 genes) from ten DDR-deficient cancer cell lines, we show that our identified genes are enriched among the top quartile of essential genes in these cell lines, implying that our inferred genes are highly likely to be (synthetic) lethal upon knockdown in these cell lines. Among the inferred targets are tousled-like kinase 2 (TLK2) and the deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7) whose overexpression correlates with poor survival in cancers.
CONCLUSION: Mutual exclusivity between frequently occurring genetic events identifies synthetic lethal combinations in cancers. These identified genes are essential in cell lines, and are potential candidates for targeted cancer therapy. Availability:

Chen ST, Okada M, Nakato R, et al.
The Deubiquitinating Enzyme USP7 Regulates Androgen Receptor Activity by Modulating Its Binding to Chromatin.
J Biol Chem. 2015; 290(35):21713-23 [PubMed] Free Access to Full Article Related Publications
The androgen receptor (AR), a nuclear receptor superfamily transcription factor, plays a key role in prostate cancer. AR signaling is the principal target for prostate cancer treatment, but current androgen-deprivation therapies cannot completely abolish AR signaling because of the heterogeneity of prostate cancers. Therefore, unraveling the mechanism of AR reactivation in androgen-depleted conditions can identify effective prostate cancer therapeutic targets. Increasing evidence indicates that AR activity is mediated by the interplay of modifying/demodifying enzymatic co-regulators. To better understand the mechanism of AR transcriptional activity regulation, we used antibodies against AR for affinity purification and identified the deubiquitinating enzyme ubiquitin-specific protease 7, USP7 as a novel AR co-regulator in prostate cancer cells. We showed that USP7 associates with AR in an androgen-dependent manner and mediates AR deubiquitination. Sequential ChIP assays indicated that USP7 forms a complex with AR on androgen-responsive elements of target genes upon stimulation with the androgen 5α-dihydrotestosterone. Further investigation indicated that USP7 is necessary to facilitate androgen-activated AR binding to chromatin. Transcriptome profile analysis of USP7-knockdown LNCaP cells also revealed the essential role of USP7 in the expression of a subset of androgen-responsive genes. Hence, inhibition of USP7 represents a compelling therapeutic strategy for the treatment of prostate cancer.

Zhu L, Liu R, Zhang W, et al.
MicroRNA-205 regulates ubiquitin specific peptidase 7 protein expression in hepatocellular carcinoma cells.
Mol Med Rep. 2015; 12(3):4652-4656 [PubMed] Related Publications
Ubiquitin specific peptidase 7 (UPS7) has a critical role in the development and progression of cancer, at least in part, through its regulation of p53 protein stability. However, its molecular determinants remain to be elucidated. In the present study, it was identified that microRNA‑205 (miR‑205) may negatively regulate UPS7 protein levels through targeting its 3'‑untranslated region in hepatocellular carcinoma (HCC) cells. As a result, miR‑205 mimics inhibited USP7 protein levels while antisense miR‑205 enhanced USP7 protein levels, thereby modulating the p53 signaling pathway and cell proliferation levels. In conclusion, the data presents a novel molecule for the dysregulated expression of USP7 in HCC, which may assist in elucidating mechanisms underlying the tumorigenesis of HCC.

McClurg UL, Robson CN
Deubiquitinating enzymes as oncotargets.
Oncotarget. 2015; 6(12):9657-68 [PubMed] Free Access to Full Article Related Publications
Carcinogenesis is a complex process tightly regulated at multiple levels by post-translational modifications. Epigenetics plays a major role in cancer development, all stable changes to the gene expression process that are not a result of a direct change in the DNA code are described as epigenetics. Epigenetic processes are regulated by post-translational modifications including ubiquitination which can directly affect either histones or transcription factors or may target their co-factors and interacting partners exerting an indirect effect. Deubiquitination of these target proteins is equally important and alterations in this pathway can also lead to cancer development, progression and metastasis. Only the correct, unaltered balance between ubiquitination and deubiquitination ensures healthy cellular homeostasis. In this review we focus on the role of deubiquitinating (DUB) enzymes in various aspects of epigenetics including the regulation of transcription factors, histone modifications, DNA damage repair pathways and cell cycle regulation. We discuss the impact of those processes on tumourigenesis and potential therapeutic applications of DUBs for cancer treatment.

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