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Downregulation of USP39 decreases TAZ transcriptional activity. a, b Western blotting analysis of total, cytoplasmic, and nuclear fractions prepared from indicated cells. Bar graph showing the ratio of TAZ nuclear protein (normalized to Histone H3) to total protein (normalized to GAPDH) levels in modified and control (NC) cells. c Representative images of immunofluorescence for TAZ (red) in indicated cells. Nuclei are stained with DAPI (blue). Scale bars, 100 µm. d qRT-PCR analysis for expression of TAZ target genes in U87MG- or A172-sh-USP39-1 compared with controls. GAPDH was used for normalization. Student’s t-test: n.s. = not significant, *p < 0.05, **p < 0.01, ***p < 0.001
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Increasing evidence demonstrates that ubiquitin specific protease 39 (USP39) plays an oncogenic role in various human tumors. Here, using expression analysis of the publicly available Oncomine database, clinical glioma patient samples, and glioma cells, we found that USP39 was overexpressed in human gliomas. Knockdown of USP39 in glioma cells demon...
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Increasing evidence demonstrates that ubiquitin specific protease 39 (USP39) plays an oncogenic role in various human tumors. Here, using expression analysis of the publicly available Oncomine database, clinical glioma patient samples, and glioma cells, we found that USP39 was overexpressed in human gliomas. Knockdown of USP39 in glioma cells demon...
Citations
... USP39 which is reported upregulated in human head and neck cancers has carcinogenic effects in ovarian cancer, glioma, esophageal squamous cell carcinoma, renal cell carcinoma, and HCC, suggesting a key role in treatment. 12,13,[35][36][37] It has also been reported that the expression of USP39 is increased in nasopharyngeal carcinoma tissues, the overexpression of USP39 can promote the proliferation of nasopharyngeal carcinoma cells, and the expression of USP39 is regulated by the LINC00520/miR-26b-3p axis. 38 Those findings are consistent with our immunohistochemical results showing that USP39 expression was elevated in HNSCC tumor tissue. ...
Objective: Ubiquitin-specific peptidase 39 (USP39) plays a carcinogenic role in many cancers, but little research has been conducted examining whether it is involved in head and neck squamous cell carcinoma (HNSCC). Therefore, this study explored the functional role of USP39 in HNSCC. Method: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify differentially expressed proteins (DEPs) between the HNSCC tumor and adjacent healthy tissues. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to assess the functional enrichment of DEPs. Immunohistochemistry was used to detect protein expression. The viability and migration of two HNSCC cell lines, namely CAL27 and SCC25, were detected using the cell counting kit-8 assay and a wound healing assay, respectively. Quantitative real-time PCR was used to detect the expression level of signal transducer and activator of transcription 1 (STAT1) mRNA. Results: LC-MS/MS results identified 590 DEPs between HNSCC and adjacent tissues collected from 4 patients. Through GO and KEGG pathway analyses, 34 different proteins were found to be enriched in the spliceosome pathway. The expression levels of USP39 and STAT1 were significantly higher in HNSCC tumor tissue than in adjacent healthy tissue as assessed by LC-MS/MS analysis, and the increased expression of USP39 and STAT1 protein was confirmed by immunohistochemistry in clinical samples collected from 7 additional patients with HNSCC. Knockdown of USP39 or STAT1 inhibited the viability and migration of CAL27 and SCC25 cells. In addition, USP39 knockdown inhibited the expression of STAT1 mRNA in these cells. Conclusion: Our findings indicated that USP39 knockdown may inhibit HNSCC viability and migration by suppressing STAT1 expression. The results of this study suggest that USP39 may be a potential new target for HNSCC clinical therapy or a new biomarker for HNSCC.
... In contrast to PD, MDD astrocytes exhibit higher expression levels of the Ubiquitin specific protease 39 (USP39) gene, which has oncogenic effects and plays a role in various cancers, including promoting glioma Frontiers in Aging Neuroscience 08 frontiersin.org progression (Ding et al., 2019;Xiao et al., 2022). Interestingly, patients with glioma have a higher risk of developing depression , suggesting that USP39 may serve as a potential bridge between the two conditions. ...
Background
Motor symptoms are well-characterized in Parkinson’s disease (PD). However, non-motor symptoms, such as depression, are commonly observed and can appear up to 10 years before motor features, resulting in one-third of individuals being misdiagnosed with a neuropsychiatric disorder. Thus, identifying diagnostic biomarkers is crucial for accurate PD diagnosis during its prodromal or early stages.
Methods
We employed an integrative approach, combining single nucleus RNA and bulk mRNA transcriptomics to perform comparative molecular signatures analysis between PD and major depressive disorder (MDD). We examined 39,834 nuclei from PD (GSE202210) and 32,707 nuclei from MDD (GSE144136) in the dorsolateral prefrontal cortex (dlPFC) of Brodmann area 9. Additionally, we analyzed bulk mRNA peripheral blood samples from PD compared to controls (GSE49126, GSE72267), as well as MDD compared to controls (GSE39653).
Results
Our findings show a higher proportion of astrocytes, and oligodendrocyte cells in the dlPFC of individuals with PD vs. MDD. The excitatory to inhibitory neurons (E/I) ratio analysis indicates that MDD has a ratio close to normal 80/20, while PD has a ratio of 62/38, indicating increased inhibition in the dlPFC. Microglia displayed the most pronounced differences in gene expression profiles between the two conditions. In PD, microglia display a pro-inflammatory phenotype, while in MDD, they regulate synaptic transmission through oligodendrocyte-microglia crosstalk. Analysis of bulk mRNA blood samples revealed that the COL5A , MID1 , ZNF148 , and CD22 genes were highly expressed in PD, whereas the DENR and RNU1G2 genes were highly expressed in MDD. CD22 is involved in B-cell activation and the negative regulation of B-cell receptor signaling. Additionally, CD86 , which provides co-stimulatory signals for T-cell activation and survival, was found to be a commonly differentially expressed gene in both conditions. Pathway analysis revealed several immune-related pathways common in both conditions, including the complement and coagulation cascade, and B-cell receptor signaling.
Discussion
This study demonstrates that bulk peripheral immune cells play a role in both conditions, but neuroinflammation in the dlPFC specifically manifests in PD as evidenced by the analysis of single nucleus dlPFC datasets. Integrating these two omics levels offers a better understanding of the shared and distinct molecular pathophysiology of PD and MDD in both the periphery and the brain. These findings could lead to potential diagnostic biomarkers, improving accuracy and guiding pharmacological treatments.
... Although USP39 was initially identified as a DUB without ubiquitin hydrolysis activity, other studies have suggested that it plays a role in RNA splicing and oncogenesis in multiple malignant tumors [157,158]. Intriguingly, USP39 stabilizes SP1, ZEB1, and FOXM1 through its deubiquitination activity, thus supporting the progression of hepatocellular carcinoma and breast cancer [159][160][161]. Silencing USP39 expression hinders MGC-803 GC cell proliferation and induces G2/M arrest and PARP cleavage [60]. ...
Gastric cancers (GCs) are malignant tumors with a high incidence that threaten global public health. Despite advances in GC diagnosis and treatment, the prognosis remains poor. Therefore, the mechanisms underlying GC progression need to be identified to develop prognostic biomarkers and therapeutic targets. Ubiquitination, a post-translational modification that regulates the stability, activity, localization, and interactions of target proteins, can be reversed by deubiquitinases (DUBs), which can remove ubiquitin monomers or polymers from modified proteins. The dysfunction of DUBs has been closely linked to tumorigenesis in various cancer types, and targeting certain DUBs may provide a potential option for cancer therapy. Multiple DUBs have been demonstrated to function as oncogenes or tumor suppressors in GC. In this review, we summarize the DUBs involved in GC and their associated upstream regulation and downstream mechanisms and present the benefits of targeting DUBs for GC treatment, which could provide new insights for GC diagnosis and therapy.
... Family member ubiquitin-specific peptidase 39 (USP39) is the homolog of Sad1p in yeast, also known as the human 65-kDa SRrelated protein (98,99). The structure of USP39 includes a central zinc finger ubiquitin domain and a canonical UCH domain (100). ...
According to GLOBOCAN 2021 cancer incidence and mortality statistics compiled by the International Agency for Research on Cancer, hepatocellular carcinoma (HCC) is the most common malignancy in the human liver and one of the leading causes of cancer death worldwide. Although there have been great advances in the treatment of HCC, such as regofenib, sorafenib, and lomvatinib, which have been developed and approved for the clinical treatment of advanced or metastatic HCC. However, they only prolong survival by a few months, and patients with advanced liver cancer are susceptible to tumor invasion metastasis and drug resistance. Ubiquitination modification is a type of post-translational modification of proteins. It can affect the physiological activity of cells by regulating the localization, stability and activity of proteins, such as: gene transcription, DNA damage signaling and other pathways. The reversible process of ubiquitination is called de-ubiquitination: it is the process of re-releasing ubiquitinated substrates with the participation of de-ubiquitinases (DUBs) and other active substances. There is growing evidence that many dysregulations of DUBs are associated with tumorigenesis. Although dysregulation of deuquitinase function is often found in HCC and other cancers, The mechanisms of action of many DUBs in HCC have not been elucidated. In this review, we focused on several deubiquitinases (DUBs) associated with hepatocellular carcinoma, including their structure, function, and relationship to hepatocellular carcinoma. hepatocellular carcinoma was highlighted, as well as the latest research reports. Among them, we focus on the USP family and OTU family which are more studied in the HCC. In addition, we discussed the prospects and significance of targeting DUBs as a new strategy for the treatment of hepatocellular carcinoma. It also briefly summarizes the research progress of some DUB-related small molecule inhibitors and their clinical application significance as a treatment for HCC in the future.
... As a splicing factor, USP39 was reported to be a regulator of EGFR pre-mRNA splicing [13]. USP39 has also been implicated in the mRNA maturation of TAZ and VEGF-A165b [14,15]. ...
Esophageal squamous cell carcinoma (ESCC) is an aggressive epithelial malignancy and the underlying molecular mechanisms remain elusive. Here, we identify that the ubiquitin-specific protease 39 (USP39) drives cell growth and chemoresistance by functional screening in ESCC, and that high expression of USP39 correlates with shorter overall survival and progression-free survival. Mechanistically, we provide evidence for the role of USP39 in alternative splicing regulation. USP39 interacts with several spliceosome components. Integrated analysis of RNA-seq and RIP-seq reveals that USP39 regulates the alternative splicing events. Taken together, our results indicate that USP39 functions as an oncogenic splicing factor and acts as a potential therapeutic target for ESCC.
... Ubiquitin-specific protease 39 (USP39) plays a carcinogenic effect in various human tumors and can promote tumor cell growth, invasion, and migration (30). In NPC, LINC00520 is upregulated in NPC tissues and cells, and LINC00520 can sponge miR-26b-3p, thereby increasing the expression of USP39. ...
Long non-coding RNA (lncRNA) is important in the study of cancer mechanisms. LINC00520 is located on human chromosome 14q22.3 and is a highly conserved long non-coding RNA. LINC00520 is widely expressed in various tissues. The expression of LINC00520 is regulated by transcription factors such as Sp1, TFAP4, and STAT3. The high expression of LINC00520 is significantly related to the risk of 11 cancers. LINC00520 can competitively bind 10 miRNAs to promote tumor cell proliferation, invasion, and migration. In addition, LINC00520 is involved in the regulation of P13K/AKT and JAK/STAT signaling pathways. The expression of LINC00520 is significantly related to the clinicopathological characteristics and prognosis of tumor patients and is also related to the sensitivity of HNSCC to radiotherapy. Here, this article summarizes the abnormal expression pattern of LINC00520 in cancer and its potential molecular regulation mechanism and points out that LINC00520 can be used as a potential biomarker for cancer diagnosis, prognosis, and treatment.
... It was found in our previous study that USP39 knockdown could inhibit the abnormal proliferation of prostate cancer cells by inhibiting the splicing maturation and transcriptional prolongation of EGFR mRNA [16]. Other studies have also reported that USP39 serves as the protumor factor in many malignant tumors such as gastric cancer [17], osteosarcoma [18], lung cancer [19], glioma [20], and breast cancer [21]. In addition, USP39 knockdown was found to inhibit RCC progression through blocking Akt/ERK pathways [22]. ...
Abstract Background The benefit of targeted therapy for renal cell carcinoma (RCC) is largely crippled by drug resistance. Rapid disease progression and poor prognosis occur in patients with drug resistance. New treatments demand prompt exploration for clinical therapies. Ubiquitin-specific peptidase 39 (USP39) serves as the pro-tumor factor in several previous studies of other malignant tumors. To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC. Methods We applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. USP39 knockdown or overexpression plasmids were transfected into 786-O and ACHN cells. The HUVEC received cell supernatants of 786-O and ACHN cells with knockdown or overexpression USP39.The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by affinity purification and mass spectrometry, co-immunoprecipitation and Western blot assays. Results The mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (P
... In this present study, expression of circCLSPN and miR-370-3p in human GBM tissues was discovered, and their roles were investigated in GBM cells both in vitro and in vivo. Ubiquitin-specific peptidase 39 (USP39) is generally overexpressed in multiple malignant tumors including glioma (Ding et al. 2019), and interactions among circCLSPN, miR-370-3p and USP39 were further identified. ...
... USP39 functioned oncogenic properties in varying tumors. For example, Ding et al. (Ding et al. 2019) declared that USP39 deficiency inhibited cell viability, invasion and migration of glioma U87MG, A172 and P3 cells in vitro as well as in vivo. Here, we observed that restoring USP39 could contribute to cell viability, cell cycle entrance, colony formation, wounding healing, migration and invasion of A172 and LN18 cells in spite of miR-370-3p overexpression. ...
... Here, we observed that restoring USP39 could contribute to cell viability, cell cycle entrance, colony formation, wounding healing, migration and invasion of A172 and LN18 cells in spite of miR-370-3p overexpression. Expression of USP39 was overexpressed in human GBM tissues and cells, and Ding et al. (Ding et al. 2019) further discovered the positive correlation between USP39 expression and WHO grade. However, we did not further decipher the involvement of itself in other subtypes of gliomas. ...
Glioblastoma multiforme (GBM) is the most aggressive and prevalent brain tumor in adults. The circRNA derived from CLSPN (hsa_circ_0011591, circCLSPN) is remarkably upregulated in GBM; however its functional role was uncovered yet. First, we examined expression of circCLSPN using GSE109569 database and RT-qPCR, and circCLSPN level was upregulated in human GBM tumor tissues and cells (A172 and LN18); moreover, circCLSPN showed a stable structure stability. Then, a series of loss-of-functional experiments were performed using CCK-8 assay, colony formation assay, flow cytometry, scratch wound assay, and transwell assay. Consequently, circCLSPN silencing suppressed cell viability, colony formation ability, cell cycle progression, migration, and invasion of A172 and LN18 cells in vitro, and promoted apoptosis rate. Allied with those were decreased B cell lymphoma-2 (Bcl-2), matrix metalloproteinase-2 (MMP2) and MMP9 expression, and elevated Bcl-2-associated X protein (Bax) level. According to dual-luciferase reporter assay and RNA pull-down assay, miR-370-3p was identified to be targeted and sponged by circCLSPN, and further targeted and negatively regulated USP39. Functionally, overexpressing miR-370-3p could mimic in vitro effects of circCLSPN interference. Rescue experiments revealed that blocking miR-370-3p could partially reverse the suppression of circCLSPN knockdown on cell growth, migration and invasion, and role of miR-370-3p overexpression was abrogated by restoring USP39. In vivo, circCLSPN knockdown hindered tumor growth of LN18 cells by affecting miR-370-3p, USP39, MMP2 and MMP9 expression. In conclusion, circCLSPN elicited an oncogenic role in tumorigenesis and malignant progression of human GBM cells through circCLSPN-miR-370-3p-USP39 pathway.
... In this context, the experimental verification of proteolytic activity and biological function is essential. For instance, USP39 (widely known as Sad1p in yeast) lacks all conserved catalytic residues; however, studies have demonstrated a pivotal role for the enzyme in mRNA splicing [29,30] and tumor progression [31]. ...
The ubiquitin-proteasome system regulates biological processes in normal and diseased states. Recent investigations have focused on ubiquitin-dependent modifications and their impacts on cellular function, commitment, and differentiation. Ubiquitination is reversed by deubiquitinases, including ubiquitin-specific peptidases (USPs), whose roles have been widely investigated. In this review, we explore recent findings highlighting the regulatory functions of USPs in osteoblasts and providing insight into the molecular mechanisms governing their actions during bone formation. We also give a brief overview of our work on USP53, a target of PTH in osteoblasts and a regulator of mesenchymal cell lineage fate decisions. Emerging evidence addresses questions pertaining to the complex layers of regulation exerted by USPs on osteoblast signaling. We provide a short overview of our and others’ understanding of how USPs modulate osteoblastogenesis. However, further studies using knockout mouse models are needed to fully understand the mechanisms underpinning USPs actions.
... Moreover, other studies have suggested that USP39 functions as an oncogenic factor in numerous cancers including breast (16), liver (17), medullary thyroid (18), lung (19), prostate (20), oral squamous cell (21) and renal cell carcinomas (22). For example, USP39 promotes prostate cancer cell tumorigenesis by facilitating EGFR mRNA maturation and transcriptional elongation (20), whereas in glioma it promotes progression by facilitating TAZ mRNA maturation (23). Our previous research in melanoma also implicated USP39 in disease progression through regulating cell cycle and apoptosis via ERK1/2 signaling (24). ...
... Since USP39 is involved in the pre-mRNA splicing of certain genes (20,23), we hypothesized that USP39 also regulates Rictor pre-mRNA splicing. To test this, we designed qRT-PCR primers that would distinguish the levels of unspliced pre-mRNA (intron [4][5] and mature spliced mRNA (exon 4-5 junction) ( Figure 5A). ...
... Because USP39 has been shown to be necessary for pre-mRNA splicing in particular genes including aurora B and Rb1 (14,15), it was natural to examine for changes in Rictor mRNA splicing. One approach used to determine the splicing rate of pre-mRNA involves comparing pre-mRNA and mature mRNA transcript levels by examining the presence of transcripts containing or lacking intronic sequences (20,23,39). Focusing on the intron 4-5/exon 4-5 ratio we found that Rictor pre-mRNA was upregulated following USP39 knockdown, indicating a role for USP39 in the efficient maturation of Rictor mRNA. ...
Spliceosomes are large RNA-protein molecular complexes which mediate splicing of pre-mRNA in eukaryotic cells. Their function is frequently altered in cancer, providing opportunities for novel therapeutic approaches. The ubiquitin specific protease 39 (USP39) is a highly conserved deubiquitylation family member that plays an essential role in pre-mRNA splicing where it serves to assemble the mature spliceosome complex. Previous studies have reported that USP39 acts in an oncogenic manner where it contributes to cancer progression and predicts poor prognosis in various human tumor types. Here we report that USP39 is differentially upregulated in human esophageal squamous cell carcinoma (ESCC) and its expression is significantly associated with clinicopathological characteristics including differentiation status and TNM stage. We found the USP39 upregulation was maintained in ESCC cell lines where it functioned to promote cancer cell growth in vitro and in xenografts. RNA-seq analyses identified that mTOR pathway activation was affected by shRNA-mediated silencing of USP39. Subsequent biochemical analyses demonstrated that USP39 regulates the activity of mTORC2 by selectively enhancing the splicing and maturation of Rictor mRNA, although not other key mTORC components. Together, our report proposes USP39 as a biomarker and oncogenic factor in ESCC, with a potential for targeting the USP39/mTOR2/Rictor axis as a therapeutic strategy. Furthermore, our study adds ESCC to the list of cancers where USP39 contributes to tumorigenesis and progression.
