USP7: Target Validation and Drug Discovery for Cancer Therapy

Zhou, Jing; Wang, Jinzheng; Chen, Chao; Yuan, Haoliang; Wen, Xiaoan; Sun, Hongbin

doi:10.2174/1573406413666171020115539

Cited by 82 publications

(77 citation statements)

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“…Therefore, it remains to be determined whether USP7 inhibitors can be safely used to extend health span and treat age-related diseases, particularly because older people are more susceptible to adverse drug effects than younger individuals. Since USP7 inhibitors are developed primarily for oncology (Zhou et al, 2018), In conclusion, we reveal that USP7 is a novel senolytic target, and USP7 inhibition can selectively kill some SnCs with p53 downregulation in vitro and clear SnCs induced by chemotherapy in mice in part by destabilizing MDM2 to increase p53 expression. However, not all cells reduce their p53 expression when they become senescent (Rufini et al, 2013).…”

Section: Discussionmentioning

confidence: 80%

“…With an increasing interest and effort in the development of USP7 inhibitors for cancer therapy (Chauhan et al, ; Fan et al, ; Tavana et al, ), more specific and potent USP7 inhibitors may become available in the near future. However, USP7 is expressed in many tissues and regulates other substrates that have different physiological functions (Zhou et al, ). Therefore, it remains to be determined whether USP7 inhibitors can be safely used to extend health span and treat age‐related diseases, particularly because older people are more susceptible to adverse drug effects than younger individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it remains to be determined whether USP7 inhibitors can be safely used to extend health span and treat age‐related diseases, particularly because older people are more susceptible to adverse drug effects than younger individuals. Since USP7 inhibitors are developed primarily for oncology (Zhou et al, ), a more viable approach to use USP7 inhibitors as senolytic agents may be to clear SnCs induced by chemotherapy because such cells can contribute to chemotherapy‐induced toxicity and promote tumor relapse and metastasis in part via the SASP. This suggestion is supported by our finding that treatment of mice with the USP7 inhibitor P5091 effectively eliminated SnCs and reduced the expression of SASP factors caused by DOX.…”

Section: Discussionmentioning

confidence: 99%

“…The results from our studies also suggest that p53 may medi- inhibitors may become available in the near future. However, USP7 is expressed in many tissues and regulates other substrates that have different physiological functions (Zhou et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

et al. 2020

Aging Cell

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The accumulation of senescent cells (SnCs) is a causal factor of various age‐related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin‐specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro‐apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL‐XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence‐associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy‐induced toxicities and treat age‐related diseases.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

et al. 2020

Aging Cell

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“…These proteins belong to a large family of cysteine proteases which deubiquitinate and reverse the degradation of proteins. In particular, USP7 deubiquitinates p53 and WASH (part of the Wiskott-Aldrich Syndrome protein family), suggesting its role in disrupting tumor suppression pathways [23]. Several PCGs associated with heat-shock proteins (HSPs) such as DNAJC13, Sacsin Molecular Chaperone (SACS), HSPA4, and HSPA4L were up-regulated.…”

Section: Enriched Canonical Pathways Following Exposure To Pbdes Citmentioning

confidence: 99%

Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism

Zhang

Kelly

et al. 2020

PLoS ONE

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Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are humanderived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpharetinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.

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USP7 reduces the level of nuclear DICER, impairing DNA damage response and promoting cancer progression

Liu,

Lu,

Yang

et al. 2023

Molecular Oncology

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Endoribonuclease DICER is an RNase III enzyme that mainly processes microRNAs in the cytoplasm, but also participates in nuclear functions such as chromatin remodeling, epigenetic modification and DNA damage repair. The expression of nuclear DICER is low in most human cancers, suggesting a tight regulation mechanism that is not well understood. Here, we found that ubiquitin carboxyl‐terminal hydrolase 7 (USP7), a deubiquitinase, bounded to DICER and reduced its nuclear protein level by promoting its ubiquitination and degradation through MDM2, a newly identified E3 ubiquitin‐protein ligase for DICER. This USP7‐MDM2‐DICER axis impaired histone γ‐H2AX signaling and the recruitment of DNA damage response (DDR) factors, possibly by influencing the processing of small DDR noncoding RNAs. We also showed that this negative regulation of DICER by USP7 via MDM2 was relevant to human tumors using cellular and clinical data. Our findings revealed a new way to understand the role of DICER in malignant tumor development and may offer new insights for diagnosis, treatment and prognosis of cancers.

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USP7: Target Validation and Drug Discovery for Cancer Therapy

Abstract: Taken together, USP7 is a promising therapeutic target and USP7 inhibitors hold promise as a new approach to cancer therapy.

Cited by 82 publications

References 0 publications

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism

USP7 reduces the level of nuclear DICER, impairing DNA damage response and promoting cancer progression

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