USP5 Sustains the Proliferation of Glioblastoma Through Stabilization of CyclinD1

Li, Gen; Yang, Tianquan; Chen, Yanling; Wu, Di; Hu, Xiaohan; Feng, Chen-Xi; Xu, Lixiao; Li, Mei; Li, Gang; Jin, Meifang; Xu, Yunyun; Zhang, Rui; Qian, Guanghui; Pan, Jian

doi:10.3389/fphar.2021.720307

Cited by 19 publications

(17 citation statements)

References 67 publications

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“…In the process of neoplasm formation, proliferation of initiated tumor cells plays a critical role in the initiation stage and subsequent promotion and progression stages [ 32 ]. Defeating proliferation of glioblastoma cells by precisely targeting a molecule of ubiquitin-specific protease, one of the deubiquitinating enzymes, could be a potential strategy for treating GBM [ 33 ]. Likewise, rapid proliferation of residual cells after surgical removal of a primary tumor is a leading cause explaining malignance of glioblastomas, poor prognosis of GBM therapy, and tumor recurrence [ 3 , 4 , 5 ].…”

Section: Discussionmentioning

confidence: 99%

Contribution of the Testosterone Androgen Receptor–PARD3B Signaling Axis to Tumorigenesis and Malignance of Glioblastoma Multiforme through Stimulating Cell Proliferation and Colony Formation

Yang

Chen

Liu

et al. 2022

JCM

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Background: Glioblastoma multiforme (GBM) is the most common and malignant brain tumor with very poor prognoses. After surgical resection of the primary tumor, rapid proliferation of residual glioblastoma cells is a critical cause explaining tumor malignance and recurrence. In this study, we evaluated de novo roles of the testosterone androgen receptor (AR)–PARD3B signaling axis in the tumorigenesis and malignance of human GBM and the possible related mechanisms. Methods: AR and PARD3B gene expressions and their correlations were mined from The Cancer Genome Atlas (TCGA) database and analyzed using the UALCAN system. Analyses using a real-time PCR, cell proliferation, and colony formation and a loss-of-function strategy by suppressing AR activity with its specific inhibitor, enzalutamide, were then carried out to determine roles of the testosterone AR–PARD3B signaling axis in tumor malignance. Results: Expressions of AR, PARD3B mRNA, and proteins in human GBM tissues were upregulated compared to normal human brain tissues. In contrast, levels of AR and PARD3B mRNA in most TCGA pan-cancer types were downregulated compared to their respective normal tissues. Interestingly, a highly positive correlation between AR and PARD3B gene expressions in human GBM was identified. The results of a bioinformatics search further showed that there were five AR-specific DNA-binding elements predicted in the 5′ promoter of the PARD3B gene. Regarding the mechanisms, exposure of human glioblastoma cells to testosterone induced AR and PARD3B gene expressions and successively stimulated cell proliferation and colony formation. Suppressing AR activity concurrently resulted in significant attenuations of testosterone-induced PARD3B gene expression, cell proliferation, and colony formation in human glioblastoma cells. Conclusions: This study showed the contribution of the testosterone AR–PARD3B signaling axis to the tumorigenesis and malignance of human GBM through stimulating cell proliferation and colony formation. Therefore, the AR-PARD3B signaling axis could be targeted for potential therapy for human GBM.

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Section: Discussionmentioning

confidence: 99%

Contribution of the Testosterone Androgen Receptor–PARD3B Signaling Axis to Tumorigenesis and Malignance of Glioblastoma Multiforme through Stimulating Cell Proliferation and Colony Formation

Yang

Chen

Liu

et al. 2022

JCM

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“…In this regard, knockdown of USP5 inhibits SLUG deubiquitination, while overexpression of USP5 promotes SLUG stability and EMT in vitro and in vivo [ 67 ]. In glioblastoma multiforme, USP5 plays a critical role in tumorigenesis and progression by stabilizing CyclinD1 protein [ 68 ]. USP5 also deubiquitinates and stabilizes c-Maf, a transcription factor related to tumor and immune cell differentiation and suppresses apoptosis in multiple myeloma cells [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

USP5 enhances SGTA mediated protein quality control

Hill

Nyathi²

2022

PLoS ONE

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Mislocalised membrane proteins (MLPs) present a risk to the cell due to exposed hydrophobic amino acids which cause MLPs to aggregate. Previous studies identified SGTA as a key component of the machinery that regulates the quality control of MLPs. Overexpression of SGTA promotes deubiqutination of MLPs resulting in their accumulation in cytosolic inclusions, suggesting SGTA acts in collaboration with deubiquitinating enzymes (DUBs) to exert these effects. However, the DUBs that play a role in this process have not been identified. In this study we have identified the ubiquitin specific peptidase 5 (USP5) as a DUB important in regulating the quality control of MLPs. We show that USP5 is in complex with SGTA, and this association is increased in the presence of an MLP. Overexpression of SGTA results in an increase in steady-state levels of MLPs suggesting a delay in proteasomal degradation of substrates. However, our results show that this effect is strongly dependent on the presence of USP5. We find that in the absence of USP5, the ability of SGTA to increase the steady state levels of MLPs is compromised. Moreover, knockdown of USP5 results in a reduction in the steady state levels of MLPs, while overexpression of USP5 increases the steady state levels. Our findings suggest that the interaction of SGTA with USP5 enables specific MLPs to escape proteasomal degradation allowing selective modulation of MLP quality control. These findings progress our understanding of aggregate formation, a hallmark in a range of neurodegenerative diseases and type II diabetes, as well as physiological processes of aggregate clearance.

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“…GBM cells (5 × 10 4 /well) were seeded into 24-well plates and treated with GNE987 or DMSO for 3 days, then stained by the EdU staining kit (BeyoClick™ EdU-488 Cell Proliferation Assay kit, Beyotime, China) according to a previous protocol [ 14 ]. Cells were treated with EdU working solution for 2 h, 4% paraformaldehyde for about 10 min, 3% BSA for 1 h, and then A 30 min click reaction at room temperature away from light, and DAPI for 5 min.…”

Section: Methodsmentioning

confidence: 99%

An inhibitor of BRD4, GNE987, inhibits the growth of glioblastoma cells by targeting C-Myc and S100A16

Yang

et al. 2022

Cancer Chemother Pharmacol

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Purpose Among children, glioblastomas (GBMs) are a relatively common type of brain tumor. BRD4 expression was elevated in GBM and negatively correlated with the prognosis of glioma. We investigated the anti-GBM effects of a novel BRD4 inhibitor GNE987. Methods We evaluated the anti-tumor effect of GNE987 in vitro and in vivo by Western blot, CCK8, flow cytometry detection, clone formation, the size of xenografts, and Ki67 immunohistochemical staining, and combined ChIP-seq with RNA-seq techniques to find its anti-tumor mechanism. Results In vitro experiments showed that GNE987 significantly degraded BRD4, inhibited the proliferation of GBM cells, blocked the cell cycle, and induced apoptosis. Similarly, in vivo experiments, GNE987 also inhibited GBM growth as seen from the size of xenografts and Ki67 immunohistochemical staining. Based on Western blotting, GNE987 can significantly reduce the protein level of C-Myc; meanwhile, we combined ChIP-seq with RNA-seq techniques to confirm that GNE987 downregulated the transcription of S100A16 by disturbing H3K27Ac. Furthermore, we validated that S100A16 is indispensable in GBM growth. Conclusion GNE987 may be effective against GBM that targets C-Myc expression and influences S100A16 transcription through downregulation of BRD4.

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USP5 Sustains the Proliferation of Glioblastoma Through Stabilization of CyclinD1

Cited by 19 publications

References 67 publications

Contribution of the Testosterone Androgen Receptor–PARD3B Signaling Axis to Tumorigenesis and Malignance of Glioblastoma Multiforme through Stimulating Cell Proliferation and Colony Formation

Contribution of the Testosterone Androgen Receptor–PARD3B Signaling Axis to Tumorigenesis and Malignance of Glioblastoma Multiforme through Stimulating Cell Proliferation and Colony Formation

USP5 enhances SGTA mediated protein quality control

An inhibitor of BRD4, GNE987, inhibits the growth of glioblastoma cells by targeting C-Myc and S100A16

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