Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects

Khusbu, Farjana Yeasmin; Chen, Fang-Zhi; Chen, Hanchun

doi:10.1002/cbf.3336

Cited by 26 publications

(19 citation statements)

References 123 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the possible strategies is to target the UPP for NSCLC therapy, such as DUBs 27. DUBs are responsible for cleavaging the ubiquitin chain of the substrate proteins, which balances ubiquitination and deubiquitination for determining protein fate 28. USP28 is one of the most functionally important DUBs and several potential substrates of USP28 have been identified, which play significant roles in cancer-related pathways, such as tumour progression, DNA-damage response, cell cycle, etc 5…”

Section: Discussionmentioning

confidence: 99%

<p>Ubiquitin-specific peptidase 28 enhances STAT3 signaling and promotes cell growth in non-small-cell lung cancer</p>

Li¹,

Huang²,

Wang³

et al. 2019

OTT

View full text Add to dashboard Cite

Background and objectives Ubiquitin-specific peptidase 28 (USP28) has been reported to play significant roles in several tumors, but its roles in non-small-cell lung cancer (NSCLC) is still unknown. In this study, we aimed to investigate the biological function and molecular mechanisms of USP28 in NSCLC. Materials and methods Immunoblotting analysis was used to detect relative proteins’ expression. Luciferase assay was performed to explore the activation of signal transducer and activator of transcription 3 (STAT3). Immunoprecipitation was performed to assess whether USP28 interacted with STAT3 or deubiquitinated STAT3. Quantitative real-time PCR was performed to evaluate the relative mRNA levels of STAT3 and USP28. Cycloheximide chase assay was carried out to examine whether USP28 affected the half-life of STAT3 protein. Cell Counting Kit-8 assay and xenograft model were used to assess whether USP28 regulated NSCLC cell growth. Results In this study, the deubiquitinating enzyme USP28 was found to mediate STAT3 signaling in NSCLC cells. USP28 interacted with STAT3, and increased the stability of STAT3 by inducing its deubiquitination. Further studies showed that USP28 was upregulated in both the primary tissues and cell lines of NSCLC. The Kaplan–Meier plotter also indicated that USP28 predicted a poor prognosis of NSCLC patients. Moreover, knockdown of USP28 inhibited cell growth of NSCLC cells in vitro and delayed NSCLC tumor growth in vivo. Conclusion These results demonstrated that USP28 was functional in NSCLC cells, and promoted NSCLC cell growth by inducing STAT3 signaling. This suggests that USP28 could be a novel target for NSCLC therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

<p>Ubiquitin-specific peptidase 28 enhances STAT3 signaling and promotes cell growth in non-small-cell lung cancer</p>

Li¹,

Huang²,

Wang³

et al. 2019

OTT

View full text Add to dashboard Cite

show abstract

“…USP7 is also reported as a regulator of PTEN . The involvement of overexpressed USP7 has already been identified in PCa via dysregulation of PTEN .…”

Section: Dubs For Regulating Akt Phosphorylation Pathwaymentioning

confidence: 98%

“…The DUB USP7 is identified as a multitargeted oncogenic protein . It can directly deubiquitinate and stabilize AR and protect AR from proteasomal degradation (Figure ).…”

Section: Dubs For Regulating Androgen Receptor Signalling Pathwaymentioning

confidence: 99%

“…Regulation of P53 signalling pathway by deubiquitinases (DUBs) involved in prostate cancer . P53 is a tumour suppressor gene which is prerequisite for apoptosis and cell cycle arrest by target gene transcription; USP2a deubiquitinates MDM2 and stabilizes it whereas USP7 deubiquitinates both MDM2 and P53; OTUB1 activates RhoA which directly inhibits P53 and indirectly inhibits P53 by induction of DHT; USP19 deubiquitinates and stabilizes KPC1, an E3 enzyme which is responsible for p27 degradation…”

Section: Dubs For Regulating P53 Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

Islam

Zhou

Chen

et al. 2019

Cell Biochemistry & Function

View full text Add to dashboard Cite

Prostate cancer (PCa) is the most common cancer diagnosed and the second most common cause of cancer‐related death in men worldwide. The current androgen deprivation therapy for PCa cannot fully cure this disease. Moreover, androgen receptor gene amplification and mutation are associated with PCa to develop castration‐resistant prostate cancer (CRPC). This review focuses on the deubiquitinases (DUBs) involved in PCa development and progression. For PCa development and progression, several cellular pathways are regulated by specific DUBs which are also highlighted in here. The ubiquitin‐specific proteases (USPs), a family member of DUBs mostly involved in the regulation of cellular pathways for PCa development, and the ubiquitin C‐terminal hydrolases (UCHs), another family member of DUBs, are responsible for PCa metastasis. Small molecular inhibitors against DUBs can inhibit or reduce the level of specific DUBs through the regulation of cellular pathway to treat this disease. Some small molecular inhibitors are already identified against some of the DUBs, but very few of them are clinically proved in PCa. So, to find out other DUBs involving in the regulation of PCa‐related pathways and to develop more effective small molecule inhibitors with greater potency would be a great idea to target PCa cells for future therapeutics and drug development with or without the combination of other anticancer drugs. Significance of the study This review is targeting DUB proteins which are responsible for PCa induction, proliferation, and metastasis by highlighting their signalling pathway so that the readers can get information about other mechanisms for PCa besides androgen receptor pathway and helps to find other oncogenic DUBs involving in these signalling pathways. This review also hopes to find other oncogenic DUBs involving in PCa‐related signalling pathways or to find the DUBs that can regulate multiple oncogenic signalling pathways which might be a good target for PCa therapeutics. In addition, there are some small molecule inhibitors that can inhibit the oncogenic DUBs and thus able to control the oncogenic pathways which would be a novel strategy to treat CRPC by using DUB inhibitor combined with or without other anticancer drugs.

show abstract

“…The ubiquitin-specific protease 7 (Usp7/HAUSP, for herpesvirus-associated USP) is a deubiquitinating enzyme that regulates several cellular and viral proteins, including tumor suppressor proteins (e.g., p53 and PTEN), DNA repair proteins, immune response regulatory proteins, epigenetic factors, and viral proteins (41)(42)(43). Considering the latter, Usp7 binding is indeed a common feature among viral proteins expressed by large DNA viruses (e.g., herpes simplex virus [HSV; ICP0] [44,45] [53]).…”

mentioning

confidence: 99%

The Ubiquitin-Specific Protease Usp7, a Novel Merkel Cell Polyomavirus Large T-Antigen Interaction Partner, Modulates Viral DNA Replication

Czech-Sioli

Siebels

Radau

et al. 2020

J Virol

View full text Add to dashboard Cite

Merkel cell polyomavirus (MCPyV) is the major cause for Merkel cell carcinoma (MCC), a rare but highly aggressive skin cancer predominantly found in elderly and immunosuppressed patients. The early viral gene products large T-antigen (LT) and small T-antigen (sT) are important for efficient viral DNA replication, and both contribute to transformation processes. These functions are executed mainly through interactions with host factors. Here, we identify the cellular ubiquitin-specific processing protease 7 (Usp7) as a new interaction partner of the MCPyV LT. Using glutathione S-transferase pulldown experiments, we show that MCPyV LT directly binds to Usp7 and that N- as well as C-terminal regions of LT bind to the TRAF (tumor necrosis factor receptor-associated) domain of Usp7. We demonstrate that endogenous Usp7 coprecipitates with MCPyV T-antigens and relocalizes to viral DNA replication centers in cells actively replicating MCPyV genomes. We show that Usp7 does not alter ubiquitination levels of the T-antigens; however, Usp7 binding increases the binding affinity of LT to the origin of replication, thereby negatively regulating viral DNA replication. Together, these data identify Usp7 as a restriction factor of MCPyV replication. In contrast to other DNA viruses, Usp7 does not affect MCPyV gene expression via its ubiquitination activity but influences MCPyV DNA replication solely via a novel mechanism that modulates binding of LT to viral DNA. IMPORTANCE MCPyV is the only human polyomavirus that is associated with cancer; the majority of Merkel cell cancers have a viral etiology. While much emphasis was placed on investigations to understand the transformation process by MCPyV oncoproteins and cellular factors, we have only limited knowledge of cellular factors participating in the MCPyV life cycle. Here, we describe Usp7, a cellular deubiquitination enzyme, as a new factor involved in MCPyV replication. Usp7 is known in the context of large DNA tumor viruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma herpesvirus, to restrict viral replication. Similar to EBV, where Usp7 binding to EBNA1 increases EBNA1 binding affinity to viral DNA, we find MCPyV LT binding to the origin of replication to be increased in the presence of Usp7, resulting in restriction of viral DNA replication. However, Usp7-induced restriction of MCPyV replication is independent of its enzymatic activity, thereby constituting a novel mechanism of Usp7-induced restriction of viral replication.

show abstract

Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects

Cited by 26 publications

References 123 publications

<p>Ubiquitin-specific peptidase 28 enhances STAT3 signaling and promotes cell growth in non-small-cell lung cancer</p>

<p>Ubiquitin-specific peptidase 28 enhances STAT3 signaling and promotes cell growth in non-small-cell lung cancer</p>

Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

The Ubiquitin-Specific Protease Usp7, a Novel Merkel Cell Polyomavirus Large T-Antigen Interaction Partner, Modulates Viral DNA Replication

Contact Info

Product

Resources

About