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USP39 is highly expressed in human HCC tissues and correlated with poor prognosis. A Representative images (magnification, ×10 and ×40) of IHC staining for USP39 in HCC tissues and normal adjacent tissues from 25 patients. B Relative IHC staining for
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Emerging evidence suggests that USP39 plays an important role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanism by which USP39 promotes HCC progression has not been well defined, especially regarding its putative ubiquitination function. Zinc-finger E-box-binding homeobox 1 (ZEB1) is a crucial inducer of epithel...
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... assess whether USP39 plays an essential role in the development of HCC, IHC analysis was performed to detect the USP39 expression level in 25 human HCC samples. The analysis showed that USP39 protein displayed a higher expression level in most clinical HCC samples when compared to normal adjacent tissues from the 25 patient samples (Fig. 1A, B). USP39 positive staining was observed in the cell nucleus of HCC tissues. We also assessed the correlation between USP39 expression and 364 HCC patients' clinicopathological parameters such as tumor grade and prognosis based on the TCGA database. As shown in Fig. 1C, USP39 expression was increased with advanced clinical grades of HCC. ...
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... samples when compared to normal adjacent tissues from the 25 patient samples (Fig. 1A, B). USP39 positive staining was observed in the cell nucleus of HCC tissues. We also assessed the correlation between USP39 expression and 364 HCC patients' clinicopathological parameters such as tumor grade and prognosis based on the TCGA database. As shown in Fig. 1C, USP39 expression was increased with advanced clinical grades of HCC. Moreover, Kaplan-Meier survival analysis revealed that HCC patients with high USP39 expression had a worse OS than those with low USP39 expression (Fig. 1D). The median OS time of HCC patients with high USP39 expression was ~37.8 months, which was markedly shorter ...
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... 364 HCC patients' clinicopathological parameters such as tumor grade and prognosis based on the TCGA database. As shown in Fig. 1C, USP39 expression was increased with advanced clinical grades of HCC. Moreover, Kaplan-Meier survival analysis revealed that HCC patients with high USP39 expression had a worse OS than those with low USP39 expression (Fig. 1D). The median OS time of HCC patients with high USP39 expression was ~37.8 months, which was markedly shorter than those with low USP39 expression (~70.5 months). These results indicated a potentially critical role of USP39 in the development of HCC and suggested that USP39 may be a valuable prediction factor for poor prognosis in ...
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... lentiviral shRNA approach. The knockdown efficiency of USP39 was confirmed by RT-PCR and western blotting ( Fig. 2A, B). MTT and colony formation assays were performed to assess the effect of USP39 knockdown on cell proliferation. The MTT results showed that silencing USP39 expression significantly inhibited the proliferative ability of HCC cells (Figs. 2C and S1). Consistently, colony formation assays demonstrated that USP39 knockdown dramatically restrained the ability of cells to form colonies (Fig. 2D, E). Wound-healing and transwell assays confirmed that USP39 knockdown remarkably suppressed the migration capacities of HCC cells (Fig. 2F-I). These results suggested that USP39 contributed ...
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Background:
The homeobox (HOX) gene family has been found to be involved in human cancers. However, its involvement in hepatocellular carcinoma (HCC) has not been well documented. Here, we comprehensively evaluated the role of HOXs in HCC.
Methods:
RNA sequencing profile of TCGA-LIHC and LIRI-JP were obtained from the Cancer Genome Atlas (TCGA)...
Citations
... In summary, E3 ubiquitin ligase plays a crucial role in cells as a key regulator of protein degradation pathway [91]. In recent years, more and more studies have shown that E3 ubiquitin ligase plays an important role in the occurrence and development of liver cancer [92,93]. By specifically identifying and labeling target proteins for ubiquitination, it affects their stability and function, and thus plays a key role in the proliferation, survival, invasion and metastasis of liver cancer cells. ...
Hepatocellular carcinoma (HCC) presents a significant global health challenge due to its high incidence, poor prognosis, and limited treatment options. As a pivotal regulator of protein stability, E3 ubiquitin ligase plays a crucial role in tumorigenesis and development. This review provides an overview of the latest research on the involvement of E3 ubiquitin ligase in hepatocellular carcinoma and elucidates its significance in hepatocellular carcinoma cell proliferation, invasion, and evasion from immune surveillance. Special attention is given to the functions of RING, HECT, and RBR E3 ubiquitin ligases and their association with hepatocellular carcinoma progression. By dissecting the molecular mechanisms and regulatory networks governed by E3 ubiquitin ligase, several potential therapeutic strategies are proposed: including the development of specific inhibitors targeting E3 ligases; augmentation of their tumor suppressor activity through drug or gene therapy; utilization of E3 ubiquitin ligase to modulate immune checkpoint proteins for improved efficacy of immunotherapy; combination strategies integrating traditional therapies with E3 ubiquitin ligase inhibitors; as well as biomarker development based on E3 ubiquitin ligase activity. Furthermore, this review discusses the prospect of overcoming drug resistance in hepatocellular carcinoma treatment through these novel approaches. Overall, this review establishes a theoretical foundation and offers fresh insights into harnessing the potential of E3 ubiquitin ligase for treating hepatocellular carcinoma while highlighting future research directions that pave the way for clinical translation studies and new drug discoveries.
... Mechanistically, TRIM26 functioned as an antagonistic protein of USP39. TRIM26 and USP39 maintain the protein level of ZEB1 by controlling its ubiquitination, hence influencing the development of HCC [22]. Nevertheless, the specific function and potential mechanism by which TRIM26 involves in the progression of ccRCC have not yet been fully understood. ...
Background
Tripartite motif-containing 26 (TRIM26), a member of the TRIM protein family, exerts dual function in several types of cancer. Nevertheless, the precise role of TRIM26 in clear cell renal cell carcinoma (ccRCC) has not been investigated.
Methods
The expression of TRIM26 in ccRCC tissues and cell lines were examined through the use of public resources and experimental validation. The impacts of TRIM26 on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process were determined via CCK-8, colony formation, EdU incorporation, wound healing, Transwell invasion, Western blot, and Immunofluorescence assays. RNA-seq followed by bioinformatic analyses were used to identify the downstream pathway of TRIM26. The interaction between TRIM26 and ETK was assessed by co-immunoprecipitation, qRT-PCR, Western blot, cycloheximide (CHX) chase, and in vivo ubiquitination assays.
Results
We have shown that TRIM26 exhibits a downregulation in both ccRCC tissues and cell lines. Furthermore, this decreased expression of TRIM26 is closely linked to unfavorable overall survival and diseases-free survival outcomes among ccRCC patients. Gain- and loss-of-function experiments demonstrated that increasing the expression of TRIM26 suppressed the proliferation, migration, invasion, and EMT process of ccRCC cells. Conversely, reducing the expression of TRIM26 had the opposite effects. RNA sequencing, coupled with bioinformatic analysis, revealed a significant enrichment of the mTOR signaling pathway in the control group compared to the group with TRIM26 overexpression. This finding was then confirmed by a western blot assay. Subsequent examination revealed that TRMI26 had a direct interaction with ETK, a non-receptor tyrosine kinase. This interaction facilitated the ubiquitination and degradation of ETK, resulting in the deactivation of the AKT/mTOR signaling pathway in ccRCC. ETK overexpression counteracted the inhibitory effects of TRIM26 overexpression on cell proliferation, migration, and invasion.
Conclusion
Our results have shown a novel mechanism by which TRIM26 hinders the advancement of ccRCC by binding to and destabilizing ETK, thus leading to the deactivation of AKT/mTOR signaling. TRIM26 shows promise as both a therapeutic target and prognostic biomarker for ccRCC patients.
... Furthermore, USP39 was shown to facilitate the progression of HCC by inhibiting the degradation of ZEB1 (a zinc-finger E-box binding homeobox 1) through deubiquitination. 10 Another study has indicated that USP39 was significantly overexpressed in HCC tumor tissues compared to adjacent normal tissues and promoted tumor growth in HCC patients by effectively splicing FoxM1. 11 According to the research findings, USP39 protein exhibited a markedly elevated expression level in both cervical squamous cell carcinoma, in stark contrast to its expression in normal tissues. ...
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.
... By preventing ferroptosis, EIF3H may contribute to the survival of cancer cells [19]. USP39, which was in conjunction with the E3 ligase TRIM26, regulates the ubiquitination level of ZEB1 and determines the progression of HCC [20]. In addition, USP27 has been shown to stabilize SETD3, which enhances cell proliferation and contributes to HCC progression [21]. ...
STAM Binding Protein Like 1 (STAMBPL1), functions as a deubiquitinase (DUB) and plays a significant role in various types of cancers. However, its effect as a DUB participating in the HCC tumorigenesis and progression still unknown. In the study, the upregulation and strong prognosis value of STAMBPL1 were identified in HCC patients. Functionally, STAMBPL1 significantly promoted HCC cells proliferation and metastasis, and it interacts with TRAF2 and stabilize it via the deubiquitination at the K63 residue. The TRAF2 upregulation stabilized by STAMBPL1 overexpression transfers of P65 protein into the nucleus and activates the WNT/PI3K/ NF-kb signaling pathway. The 251–436 sites of STAMBPL1 particularly interact with the 294–496 sites of TRAF2, thereby exerting the function of DUB and removing the ubiquitin molecules attached to TRAF2. Our research unveiled a new function of STAMBPL1 in mediating TRAF2 deubiquitination and stabilization, thereby activating the WNT/PI3K/NF-kb signaling pathway, suggesting its potential as a novel biomarker and therapeutic target for HCC.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13062-024-00460-7.
... Initially classified as pseudo-DUBs within the USP family, both USP39 and USP52 have been the subject of reconsideration (Walden et al., 2018). As previously discussed, several studies indicate that USP39 might exhibit DUB activity via non-conserved residues (Wu et al., 2019;Peng et al., 2020;Dong et al., 2021;Li et al., 2021;Chen et al., 2024), a hypothesis confirmed for USP52 (Yang et al., 2018). Both USP39 and USP52 lack the typical catalytic triad residues (cysteine, histidine and aspartate) found in other USPs. ...
Proteases that cleave ubiquitin or ubiquitin-like proteins (UBLs) are critical players in maintaining the homeostasis of the organism. Concordantly, their dysregulation has been directly linked to various diseases, including cancer, neurodegeneration, developmental aberrations, cardiac disorders and inflammation. Given their potential as novel therapeutic targets, it is essential to fully understand their mechanisms of action. Traditionally, observed effects resulting from deficiencies in deubiquitinases (DUBs) and UBL proteases have often been attributed to the misregulation of substrate modification by ubiquitin or UBLs. Therefore, much research has focused on understanding the catalytic activities of these proteins. However, this view has overlooked the possibility that DUBs and UBL proteases might also have significant non-catalytic functions, which are more prevalent than previously believed and urgently require further investigation. Moreover, multiple examples have shown that either selective loss of only the protease activity or complete absence of these proteins can have different functional and physiological consequences. Furthermore, DUBs and UBL proteases have been shown to often contain domains or binding motifs that not only modulate their catalytic activity but can also mediate entirely different functions. This review aims to shed light on the non-catalytic, moonlighting functions of DUBs and UBL proteases, which extend beyond the hydrolysis of ubiquitin and UBL chains and are just beginning to emerge.
... Moreover, other mutations affect genes involved in the cell cycle regulation (p53, RB1) or genes regulating chromatin remodelling such as AT-Rich Interaction Domain 1A (ARID1A) and ARID2 [4,5]. Indeed, liver cancer cells frequently show important genomic defects [6][7][8], often implying deregulation of the proteasome degradation [9][10][11][12], as well as mutation or simply deregulated expression of the p53 family members [13][14][15][16][17][18] or other transcription factors [19]. Moreover, metabolism and the hypoxic pathway shows at times significant biochemical abnormalities [20]; all these are able to affect cancer progression [21,22] as well as response to therapy [23]. ...
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, occurring predominantly in patients with underlying chronic liver disease and cirrhosis. Here, we describe a case of a 62-year-old man that was admitted to our hospital and diagnosed with HCC where the cancer has already metastasized to the retroperitoneum and peritoneum. In order to better characterize the HCC, both the cancerous liver tissue and the adjacent normal liver tissue of the patient were collected and subjected to a genomic, transcriptomic and proteomic analysis. Our patient carries a highly mutated HCC, which is characterized by both somatic mutation in the following genes ALK, CDK6, TP53, PGR. In addition, we observe several molecular alterations that are associated with potential therapy resistance, for example the expression of the organic-anion-transporting polypeptide (OATP) family members B1 and B3, that mediate the transport of the anticancer drugs, has been found decreased. Overall, our molecular profiling potentially classify the patient with poor prognosis and possibly displaying resistance to pharmacological therapy.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12672-023-00850-9.
... The previously described procedure was employed to conduct Western blot analysis [76]. RIPA buffer was utilized to extract proteins, followed by quantification using a protein quantification kit based on bicinchoninic acid (BCA) (Thermo Fisher Scientific, Cat. ...
Limited studies have explored novel pancreatic cancer (PC) subtypes or prognostic biomarkers based on the altered activity of relevant signaling pathway gene sets. Here, we employed non-negative matrix factorization (NMF) to identify three immune subtypes of PC based on C7 immunologic signature gene set activity in PC and normal samples. Cluster 1, the immune-inflamed subtype, showed a higher response rate to immune checkpoint blockade (ICB) and had the lowest tumor immune dysfunction and exclusion (TIDE) scores. Cluster 2, the immune-excluded subtype, exhibited strong associations with stromal activation, characterized by elevated expression levels of transforming growth factor (TGF)-β, cell adhesion, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT) related genes. Cluster 3, the immune-desert subtype, displayed limited immune activity. For prognostic prediction, we developed an immune-related prognostic risk model (IRPM) based on four immune-related prognostic genes in pancreatic cancer, RHOF, CEP250, TSC1, and KIF20B. The IRPM demonstrated excellent prognostic efficacy and successful validation in an external cohort. Notably, the key gene in the prognostic model, RHOF, exerted significant influence on the proliferation, migration, and invasion of pancreatic cancer cells through in vitro experiments. Furthermore, we conducted a comprehensive analysis of somatic mutational landscapes and immune landscapes in PC patients with different IRPM risk scores. Our findings accurately stratified patients based on their immune microenvironment and predicted immunotherapy responses, offering valuable insights for clinicians in developing more targeted clinical strategies.
... but is essential for recruitment of the tri-snRNP to the pre-spliceosome 13 . Mounting evidence suggests that Usp39 is involved in the development of various types of cancer 14,15 . Usp39 deficient mice display early embryonic lethality with aberrant apico-basal polarity 16 , but the physiological and pathological functions of Usp39 in liver remain largely unknown. ...
Regulation of alternative splicing (AS) enables a single transcript to yield multiple isoforms that increase transcriptome and proteome diversity. Here, we report that spliceosome component Usp39 plays a role in the regulation of hepatocyte lipid homeostasis. We demonstrate that Usp39 expression is downregulated in hepatic tissues of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) subjects. Hepatocyte-specific Usp39 deletion in mice leads to increased lipid accumulation, spontaneous steatosis and impaired autophagy. Combined analysis of RNA immunoprecipitation (RIP-seq) and bulk RNA sequencing (RNA-seq) data reveals that Usp39 regulates AS of several autophagy-related genes. In particular, deletion of Usp39 results in alternative 5’ splice site selection of exon 6 in Heat shock transcription factor 1 (Hsf1) and consequently its reduced expression. Importantly, overexpression of Hsf1 could attenuate lipid accumulation caused by Usp39 deficiency. Taken together, our findings indicate that Usp39-mediated AS is required for sustaining autophagy and lipid homeostasis in the liver.
... Accumulating evidence supports the notion that aberrant dysregulation of ubiquitination induces tumorigenesis [6] . For instance, the deubiquitinating enzyme USP39 and the E3 ligase TRIM26 play a role in maintaining the level of ZEB1 ubiquitination, thereby promoting the progression of hepatocellular carcinoma [7]. In the human sapiens ubiquitin is a protein composed of 76 amino acids [8] with 7 lysine residues (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48 and Lys63) [9,10]. ...
Liver cancer is ranked as the sixth most prevalent from of malignancy globally and stands as the third primary contributor to cancer-related mortality. Metastasis is the main reason for liver cancer treatment failure and patient deaths. Speckle-type POZ protein (SPOP) serves as a crucial substrate junction protein within the cullin-RING E3 ligase complex, acting as a significant tumor suppressor in liver cancer. Nevertheless, the precise molecular mechanism underlying the role of SPOP in liver cancer metastasis remain elusive. In the current study, we identified cAMP response element binding 5 (CREB5) as a novel SPOP substrate in liver cancer. SPOP facilitates non-degradative K63-polyubiquitination of CREB5 on K432 site, consequently hindering its capacity to activate receptor tyrosine kinase MET. Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver cancer metastasis.
... On the other hand, certain TRIM proteins were reported to serve tumor-suppressive functions. For instance, TRIM3 and TRIM26 were lower expressed in HCC, and their reduced expression was correlated with aggressive tumor growth [12,13]. Similarly, TRIM62 was reported as a tumor suppressor in breast cancer and lung cancer, which can regulates cell polarity and epithelial plasticity [14,15]. ...
Background/aim
Hepatocellular carcinoma (HCC) ranks among the most prevalent malignancies worldwide and the third leading cause of cancer-related death. The TRIM (tripartite motif-containing) protein family members had been reported to be involved in carcinogenesis and tumor progression. Here we aimed to explore the expression profile of TRIM6 in HCC and investigate its clinical significance as well as underlying mechanisms.
Materials and methods
We retrospectively enrolled 138 HCC patients that underwent surgical resection in our hospital and tested protein expression level of TRIM6 through immunohistochemical staining. The correlation between TRIM6 and patients’ characteristics was assessed by Chi-square test. Log-rank test and Cox hazard regression test were conducted for univariate and multivariate survival analyses, respectively. Two human HCC cell lines, Huh7 and Hep3B, were subjected for knockdown and overexpression assays, followed by phonotype tests including proliferation and invasion. Nude mice were used to generate xenograft model to validate our findings in vivo.
Results
TRIM6 was highly expressed in HCC specimen compared to nontumorous liver tissues. Higher TRIM6 expression was correlated with larger tumor size, later tumor stage, and worse prognosis. According to the cellular experiments, TRIM6-knockdown resulted in decreased expression of cyclin B1, c-Myc, Snail, MMP2, and VEGF-A. Consistently, TRIM6-knockdown led to impaired HCC proliferation, invasion, and angiogenesis. In contrast, TRIM6 overexpression showed opposite effects. Finally, the oncogenic role of TRIM6 in HCC was validated by in vivo mice experiments.
Conclusion
TRIM6 can serve as a novel prognostic factor for HCC, which functions by multiple signaling pathways.
