USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia

Qi, Jin; Martínez, Carlos A.; Arcipowski, Kelly M.; Zhu, Yaxian; Gutierrez-Diaz, Blanca T.; Wang, Kenneth K.; Johnson, Martin P.; Volk, Andrew; Wang, Feng; Wu, Jian; Grove, Charles I.; Wang, Hui; Sokirniy, Ivan; Thomas, Paul M.; Goo, Young Ah; Abshiru, Nebiyu; Hijiya, Nobuko; Peirs, Sofie; Vandamme, Niels; Berx, Geert; Goosens, Steven; Marshall, Stacy A.; Rendleman, Emily J.; Takahashi, Yoh Hei; Wang, Lu; Rawat, Radhika; Bartom, Elizabeth T.; Collings, Clayton K.; Vlierberghe, Pieter Van; Strikoudis, Alexandros; Kelly, Stephen M.; Ueberheide, Beatrix; Mantis, Christine; Kandela, Irawati; Bourquin, Jean‐Pierre; Bornhäuser, Beat; Serafin, Valentina; Bresolin, Silvia; Paganin, Maddalena; Accordi, Benedetta; Basso, Giuseppe; Kelleher, Neil L.; Weinstock, Joseph; Kumar, Suresh; Crispino, John D.; Shilatifard, Ali; Ntziachristos, Panagiotis

doi:10.1158/1078-0432.ccr-18-1740

Cited by 72 publications

(83 citation statements)

References 114 publications

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“…Expression of deubiquitylase USP7 is reported to be a prognostic factor in osteogenic sarcoma, T-cell lymphoma and ovarian cancers [26][27][28]. Both the mRNA and protein expressions were obviously increased in HCC which is partly consistent with our results [29].…”

Section: Discussionsupporting

confidence: 90%

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

Zhang

et al. 2020

Cancer Cell Int

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Background: Ubiquitin-specific protease 7 (USP7) is a de-ubiquitin enzyme that plays an essential role in multiple cancers and becomes a target for treatment. However, the role of USP7 and its therapeutic value for HCC remains unclear. Methods: USP7 expression was examined in HCC tissues by western blot and immunohistochemistry. The correlation of USP7 and HCC prognosis was analyzed by Kaplan-Meier survival method. Mass spectrometry was determined and cell proliferation and tumorigenicity assays were conducted in vitro and in vivo treated by P22077 and sgRNA-USP7. Results: USP7 expression was significantly increased in HCC and associated with its progression. Interestingly, many HCC cells are sensitive to USP7 inhibition by using P22077. P22077 treatment not only induced cell death but also inhibited cell proliferation and migration in Huh7 and SK-Hep1 cells. In a xenograft model, P22077 efficiently inhibited tumor growth. In chemo-resistant HCC cells, P22077 decreased cell sensitivity to chemotherapy. In addition, mass spectrometry reveals 224 of significantly changed proteins upon P22077 treatment. Conclusions: We demonstrate a critical role of USP7 in HCC devolvement and chemoresistance. Disruption of USP7 function results in dis-regulated several key biological processes and subsequently activates BAX. USP7 might be a novel and drug-able target in HCC.

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Section: Discussionsupporting

confidence: 90%

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

Zhang

et al. 2020

Cancer Cell Int

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“…Depletion of USP7 in HL-60 cells decreased ASXL1 protein level, suggesting that USP7 inhibitor may a potential target in AML and MDS treatment [32]. Jin reported that USP7 was overexpressed in T-ALL cells and suppression of USP7 led to significantly decrease T-ALL cell growth in vitro and in vivo by controlling the NOTCH1 protein level through deubiquitination [33]. Liu found that USP10 acted as the DUBs of SKP2 which may also promote leukemogenesis and stabilize SKP2 protein in CML cells.…”

Section: Discussionmentioning

confidence: 99%

De-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses CML cell apoptosis and contributes to Imatinib resistance

Nie

Yao

Yang

et al. 2020

J Exp Clin Cancer Res

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Background: STAT5 plays an important role in the transformation of hematopoietic cells by BCR-ABL. However, the downstream target genes activated by STAT5 in chronic myeloid leukemia (CML) cells remain largely unclear. Here, we investigated the mechanistic functional relationship between STAT5A-regulated microRNA and CML cell apoptosis. Methods: The expression of USP15, Caspase-6, STAT5A-regulated miR-202-5p and STAT5A was detected by qRT-PCR and Western blotting in CML cell lines and PBMCs of CML patients. Cell apoptosis was evaluated by flow cytometry. Both gain-and loss-of-function experiments were used to investigate the roles of USP15, miR-202-5p and STAT5A in CML. Luciferase reporter assay detected the effect of miR-202-5p on USP15 expression. Xenograft animal model was used to test the effect of anti-miR-202-5p and pimozide on K562 cell xenograft growth. Results: USP15 expression was significantly downregulated in CML cell lines and PBMCs of CML patients. Depletion of USP15 increased, whereas overexpression of USP15 reduced the resistance of CML cells to Imatinib. Further, decreased deubiquitinating activity of USP15 by USP15 downregulation led to reduced caspase-6 level, thus attenuating CML cell apoptosis. Mechanistically, miR-202-5p was upregulated in K562G cells and negatively regulated USP15 expression by directly targeting USP15 3′-UTR. Correspondingly, upregulation of miR-202-5p enhanced the resistance of CML cells to Imatinib by inhibiting cell apoptosis. Importantly, STAT5A was upregulated in CML cells and directly activated miR-202-5p transcription by binding to the pre-miR-202 promoter. Pimozide induced CML cell apoptosis and significantly reduced K562 cell xenograft growth in vivo by blocking STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis. Conclusions: we provide the first evidence that de-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses the apoptosis of CML cells, targeting this pathway might be a promising therapeutic approach for the treatment of CML.

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“…Therefore, these results argue that USP7 is a tumor suppressor in T-ALL. However, a recent report showed that USP7 directly regulates NOTCH1 stability and its intact activity might be important for the oncogenic effects of NOTCH1 complex, suggesting a leukemogenic effect of USP7 (33). In fact, small molecule inhibitor of USP7 potently inhibited T-ALL cell growth (33).…”

Section: Discussionmentioning

confidence: 99%

“…However, a recent report showed that USP7 directly regulates NOTCH1 stability and its intact activity might be important for the oncogenic effects of NOTCH1 complex, suggesting a leukemogenic effect of USP7 (33). In fact, small molecule inhibitor of USP7 potently inhibited T-ALL cell growth (33). Future mechanistic studies are warranted to reconcile these seemingly conflicting observations and to understand the exact mechanism by which USP7 influences the pathogenesis of T-ALL.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children

Qian¹,

Zhao²,

Devidas³

et al. 2019

JNCI: Journal of the National Cancer Institute

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Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

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USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia

Cited by 72 publications

References 114 publications

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

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

De-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses CML cell apoptosis and contributes to Imatinib resistance

Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children

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