The Role of the Ubiquitin Proteasome System in Glioma: Analysis Emphasizing the Main Molecular Players and Therapeutic Strategies Identified in Glioblastoma Multiforme

Maksoud, Semer

doi:10.1007/s12035-021-02339-4

Cited by 36 publications

(38 citation statements)

References 217 publications

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“…Substrate proteins are stabilized and function under the combined regulation of the ubiquitin-proteasome system (UPS) and deubiquitinating enzymes (DUBs) [7]. The regulation of most key proteins determines cell proliferation, migration and apoptosis [8]. The pathways being regulated have different results depending on the ubiquitination site.…”

Section: Open Accessmentioning

confidence: 99%

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4

Pan

et al. 2021

Cancer Cell Int

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Background Glioblastomas (GBMs) are grade IV central nervous system tumors characterized by a poor prognosis and a short median overall survival. Effective induction of GBM cell death is difficult because the GBM cell population is genetically unstable, resistant to chemotherapy and highly angiogenic. In recent studies, ubiquitin-specific protease 7 (USP7) is shown to scavenge ubiquitin from oncogenic protein substrates, so effective inhibition of USP7 may be a potential key treatment for GBM. Methods Immunohistochemistry and western blotting were used to detect the expression of USP7 in GBM tissues. In vitro apoptosis assay of USP7 inhibition was performed by western blotting, immunofluorescence, and flow cytometry. Anti-apoptotic substrates of USP7 were defined by Co-IP and TMT proteomics. Western blotting and IP were used to verify the relationship between USP7 and its substrate. In an in vivo experiment using an intracranial xenograft model in nude mice was constructed to assess the therapeutic effect of target USP7. Results Immunohistochemistry and western blotting confirmed that USP7 was significantly upregulated in glioblastoma samples. In in vitro experiments, inhibition of USP7 in GBM induced significant apoptosis. Co-IP and TMT proteomics identified a key anti-apoptotic substrate of USP7, ADP-ribosylation factor 4 (ARF4). Western blotting and IP confirmed that USP7 interacted directly with ARF4 and catalyzed the removal of the K48-linked polyubiquitinated chain that binded to ARF4. In addition, in vivo experiments revealed that USP7 inhibition significantly suppressed tumor growth and promoted the expression of apoptotic genes. Conclusions Targeted inhibition of USP7 enhances the ubiquitination of ARF4 and ultimately mediates the apoptosis of GBM cells. In a clinical sense, P5091 as a novel specific inhibitor of USP7 may be an effective approach for the treatment of GBM.

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Section: Open Accessmentioning

confidence: 99%

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4

Pan

et al. 2021

Cancer Cell Int

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“…The ubiquitinated proteins can be specially recognized by the 26S proteasome, and this leads to the proteasomal degradation of these proteins, regulating different cell processes. Many studies have revealed that the ubiquitin–proteasome system is involved in the progression of GBM 7 – 10 . A siRNA screening analysis showed that 22% of GBM-survival-relevant genes were components of the 20S and 26S proteasome subunits 11 .…”

Section: Introductionmentioning

confidence: 99%

“…NSC 144303 (G5) and NSC 632839 (F6), two DUBs inhibitors, are under pre-clinical trial 6 . Several DUBs were reported to regulate multiple cellular processes such as apoptosis, proliferation, and stemness in GBM 7 , 21 .…”

Section: Introductionmentioning

confidence: 99%

Identification of ubiquitin-specific protease 32 as an oncogene in glioblastoma and the underlying mechanisms

Chen

et al. 2022

Sci Rep

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Glioblastoma (GBM) patients present poor prognosis. Deubiquitination by deubiquitinating enzymes (DUBs) is a critical process in cancer progression. Ubiquitin-specific proteases (USPs) constitute the largest sub-family of DUBs. Evaluate the role of USP32 in GBM progression and provide a potential target for GBM treatment. Clinical significance of USP32 was investigated using Gene Expression Omnibus databases. Effects of USP32 on cell growth and metastasis were studied in vitro and in vivo. Differentially expressive genes between USP32-knockdown U-87 MG cells and negative control cells were detected using RNA sequencing and used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomic pathway enrichment analyses. Finally, RT-qPCR was used to validate the divergent expression of genes involved in the enriched pathways. USP32 was upregulated in GBM patients, being correlated to poor prognosis. USP32 downregulation inhibited cell growth and metastasis in vitro. Furthermore, USP32 knockdown inhibited tumorigenesis in vivo. In addition, UPS32 was identified as a crucial regulator in different pathways including cell cycle, cellular senescence, DNA replication, base excision repair, and mismatch repair pathways. USP32 acts as an oncogene in GBM through regulating several biological processes/pathways. It could be a potential target for GBM treatment.

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“…Recently, the UPS is emerging as a promising source for the development of new therapeutic options for GB, and in particular PROTACs represent an interesting targeted therapy for the treatment of this devastating tumor ( Bufalieri et al, 2020b ; Scholz et al, 2020 ; Maksoud 2021 ; Farrell and Jarome 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Proteolysis-Targeting Chimera (PROTAC): Is the Technology Looking at the Treatment of Brain Tumors?

Severini

Bufalieri

Infante

2022

Front. Cell Dev. Biol.

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Post-translational modifications, such as ubiquitylation, need to be tightly controlled to guarantee the accurate localization and activity of proteins. Ubiquitylation is a dynamic process primarily responsible for proteasome-mediated degradation of substrate proteins and crucial for both normal homeostasis and disease. Alterations in ubiquitylation lead to the upregulation of oncoproteins and/or downregulation of tumor suppressors, thus concurring in tumorigenesis. PROteolysis-TArgeting Chimera (PROTAC) is an innovative strategy that takes advantage by the cell’s own Ubiquitin-Proteasome System (UPS). Each PROTAC molecule is composed by a ligand that recruits the target protein of interest (POI), a ligand specific for an E3 ubiquitin ligase enzyme, and a linker that connects these units. Upon binding to the POI, the PROTAC recruits the E3 inducing ubiquitylation-dependent proteasome degradation of the POI. To date, PROTAC technology has entered in clinical trials for several human cancers. Here, we will discuss the advantages and limitations of PROTACs development and safety considerations for their clinical application. Furthermore, we will review the potential of PROTAC strategy as therapeutic option in brain tumor, focusing on glioblastoma.

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The Role of the Ubiquitin Proteasome System in Glioma: Analysis Emphasizing the Main Molecular Players and Therapeutic Strategies Identified in Glioblastoma Multiforme

Cited by 36 publications

References 217 publications

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4

Identification of ubiquitin-specific protease 32 as an oncogene in glioblastoma and the underlying mechanisms

Proteolysis-Targeting Chimera (PROTAC): Is the Technology Looking at the Treatment of Brain Tumors?

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