Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Knockdown of SENP1 inhibits HIF-1α SUMOylation and suppresses oncogenic CCNE1 in Wilms tumor

ABSTRACT: Based on our initial bioinformatics finding of the upregulated expression of sentrin-specific protease 1 (SENP1) and cyclin E1 (CCNE1) in Wilms tumor, this study aimed to illustrate the molecular mechanism of SENP1 in Wilms tumor, which involved the hypoxia-inducible factor 1α (HIF-1α)/stanniocalcin-1 (STC1)/CCNE1 axis. Wilms tumor and adjacent normal tissues were clinically collected. Gain- and loss-of-function assays were performed to evaluate the effects of the regulatory axis on malignant phenotypes of Wilms tumor cells. A mouse model of Wilms tumor xenografts was further established for in vivo substantiation. Overexpression of CCNE1 and SENP1 occurred in Wilms tumor tissues and cells. Silencing SENP1 inhibited viability and enhanced cell-cycle arrest of Wilms tumor cells. SENP1 promoted STC1 expression and upregulated CCNE1 by driving the small ubiquitin-like modifier (SUMO)ylation of HIF-1α, which ultimately promoted the malignant phenotypes of Wilms tumor cells. It was further confirmed that silencing SENP1 downregulated the expression of CCNE1 and restricted tumorigenicity of Wilms tumor cells in vivo. Taken together, SENP1 elevated STC1 expression by driving the SUMOylation of HIF-1α, thereby upregulating the expression of CCNE1 and ultimately promoting the development of Wilms tumor. Graphical abstract Wilms tumor is a frequently occurring embryonal tumor in children. This study elucidates a novel mechanism by which sentrin-specific protease 1 (SENP1) triggers the development of Wilms tumor through regulating the HIF-1α/STC1/CCNE1 axis. Herein, this study provides potential therapeutic targets for the treatment of Wilms tumor.

SUBMITTER: Zhu S

PROVIDER: S-EPMC8581455 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

SUMOylation indirectly suppresses activity of the HIF-1α pathway in intestinal epithelial cells.

Project description:The hypoxia-inducible factor (HIF) is a master regulator of the cellular transcriptional response to hypoxia. While the oxygen-sensitive regulation of HIF-1α subunit stability via the ubiquitin-proteasome pathway has been well described, less is known about how other oxygen-independent post-translational modifications impact the HIF pathway. SUMOylation, the attachment of SUMO (small ubiquitin-like modifier) proteins to a target protein, regulates the HIF pathway, although the impact of SUMO on HIF activity remains controversial. Here, we examined the effects of SUMOylation on the expression pattern of HIF-1α in response to pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG) in intestinal epithelial cells. We evaluated the effects of SUMO-1, SUMO-2, and SUMO-3 overexpression and inhibition of SUMOylation using a novel selective inhibitor of the SUMO pathway, TAK-981, on the sensitivity of HIF-1α in Caco-2 intestinal epithelial cells. Our findings demonstrate that treatment with TAK-981 decreases global SUMO-1 and SUMO-2/3 modification and enhances HIF-1α protein levels, whereas SUMO-1 and SUMO-2/3 overexpression results in decreased HIF-1α protein levels in response to DMOG. Reporter assay analysis demonstrates reduced HIF-1α transcriptional activity in cells overexpressing SUMO-1 and SUMO-2/3, whereas pretreatment with TAK-981 increased HIF-1α transcriptional activity in response to DMOG. In addition, HIF-1α nuclear accumulation was decreased in cells overexpressing SUMO-1. Importantly, we showed that HIF-1α is not directly SUMOylated, but that SUMOylation affects HIF-1α stability and activity indirectly. Taken together, our results indicate that SUMOylation indirectly suppresses HIF-1α protein stability, transcriptional activity, and nuclear accumulation in intestinal epithelial cells.

| S-EPMC10616383 | biostudies-literature

SENP1 desensitizes hypoxic ovarian cancer cells to cisplatin by up-regulating HIF-1α.

Project description:Hypoxia-inducible factor 1 alpha (HIF-1α) is closely related to chemoresistance of ovarian cancers. Although it is reported that HIF-1α can be regulated by Sentrin/SUMO-specific protease 1 (SENP1), the effects of SENP1 on HIF-1α is still controversial. In this study, we identified that SENP1 positively regulated the expression of HIF-1α by deSUMOylation and weakened the sensitivity of hypoxic ovarian cancer cells to cisplatin. These results indicate that SENP1 is a positive regulator of HIF-1α and plays a negative role in ovarian cancer chemotherapy.

| S-EPMC4637857 | biostudies-other

Knockdown of LRRN1 inhibits malignant phenotypes through the regulation of HIF-1α/Notch pathway in pancreatic ductal adenocarcinoma.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory and fatal human malignancies. Leucine-rich repeat neuronal protein-1 (LRRN1) plays a crucial role in the development of the nervous system. However, the clinical implications and biological functions of LRRN1 in PDAC remain unclear. We found that LRRN1 expression was upregulated in PDAC tissues compared with paracancerous tissues and normal pancreatic tissues through the different public databases, tissue microarray-based immunohistochemistry, and dimethylbenzanthracene-induced PDAC murine model. The expression level of LRRN1 was closely related to the overall survival and disease-free survival of PDAC patients. Cox multivariate analysis indicated that LRRN1 was an independent adverse prognostic factor. The small hairpin RNA (shRNA)-mediated LRRN1 knockdown remarkably restrained the proliferative, migratory, and invasive capacities, as well as promoted cell apoptosis and increased G0/G1 arrest in PDAC cells. The xenograft murine subcutaneous bearing model and metastasis model verified that silencing of LRRN1 effectively dampened tumor growth and metastasis in vivo. Specifically, LRRN1 exerted its biological functions through the HIF-1α/Notch signaling pathway, and LRRN1 knockdown could dampen Jagged 1-mediated Notch pathway activation. Therefore, LRRN1 could serve as the potential therapeutic or prognostic target for PDAC.

| S-EPMC8479295 | biostudies-literature

SENP1 reduces oxidative stress and apoptosis in renal ischaemia-reperfusion injury by deSUMOylation of HIF-1α.

Project description:Renal ischaemia-reperfusion injury (RIRI) is a primary cause of acute kidney damage, occurring frequently in situations like renal transplantation, yet the underlying mechanisms were not fully understood. Sentrin-specific protease 1 (SENP1) is an important member of the SENP family, which is widely involved in various diseases. However, the role of SENP1 in RIRI has been unclear. In our study, we discovered that SENP1 was involved in RIRI and reduced renal cell apoptosis and oxidative stress at elevated levels. Further mechanistic studies showed that hypoxia-inducible factor-1α (HIF-1α) was identified as a substrate of SENP1. Furthermore, SENP1 deSUMOylated HIF-1α, which reduced the degradation of HIF-1α, and exerted a renoprotective function. In addition, the protective function was lost after application of the HIF-1α specific inhibitor KC7F2. Briefly, our results fully demonstrated that SENP1 reduced the degradation of HIF-1α and attenuated oxidative stress and apoptosis in RIRI by regulating the deSUMOylation of HIF-1α, suggesting that SENP1 may serve as a potential therapeutic target for the treatment of RIRI.

| S-EPMC11358391 | biostudies-literature

NQO1 inhibits proteasome-mediated degradation of HIF-1α.

Project description:Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF-1α and inhibits the proteasome-mediated degradation of HIF-1α by preventing PHDs from interacting with HIF-1α. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1α expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1α stability in cancers.

| S-EPMC5171868 | biostudies-literature

SENP1 promotes hypoxia-induced cancer stemness by HIF-1? deSUMOylation and SENP1/HIF-1? positive feedback loop.

Project description:We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.HCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed.We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1? deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1?. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2? and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1?.Taken together, our findings suggest the significance of this positive feedback loop between HIF-1? and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.

| S-EPMC5749365 | biostudies-literature

The p38α Stress Kinase Suppresses Aneuploidy Tolerance by Inhibiting Hif-1α.

Project description:Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1α and that inhibiting Hif-1α restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1α to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.

| S-EPMC6205844 | biostudies-literature

Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis.

Project description:Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH.

| S-EPMC5806149 | biostudies-literature

Ginsenoside Rg3 inhibits pulmonary fibrosis by preventing HIF-1α nuclear localisation.

Project description:BackgroundExcessive fibroblast proliferation during pulmonary fibrosis leads to structural abnormalities in lung tissue and causes hypoxia and cell injury. However, the mechanisms and effective treatment are still limited.MethodsIn vivo, we used bleomycin to induce pulmonary fibrosis in mice. IHC and Masson staining were used to evaluate the inhibitory effect of ginsenoside Rg3 in pulmonary fibrosis. In vitro, scanning electron microscopy, transwell and wound healing were used to evaluate the cell phenotype of LL 29 cells. In addition, biacore was used to detect the binding between ginsenoside Rg3 and HIF-1α.ResultsHere, we found that bleomycin induces the activation of the HIF-1α/TGFβ1 signalling pathway and further enhances the migration and proliferation of fibroblasts through the epithelial mesenchymal transition (EMT). In addition, molecular docking and biacore results indicated that ginsenoside Rg3 can bind HIF-1α. Therefore, Ginsenoside Rg3 can slow down the progression of pulmonary fibrosis by inhibiting the nuclear localisation of HIF-1α.ConclusionsThis finding suggests that early targeted treatment of hypoxia may have potential value in the treatment of pulmonary fibrosis.

| S-EPMC7912494 | biostudies-literature

Knockdown <i>SENP1</i> Suppressed the Angiogenic Potential of Mesenchymal Stem Cells by Impacting CXCR4-Regulated MRTF-A SUMOylation and CCN1 Expression.

Project description:The angiogenic potential of mesenchymal stem cells (MSCs) is critical for adult vascular regeneration and repair, which is regulated by various growth factors and cytokines. In the current study, we report that knockdown SUMO-specific peptidase 1 (SENP1) stimulated the SUMOylation of MRTF-A and prevented its translocation into the nucleus, leading to downregulation of the cytokine and angiogenic factor CCN1, which significantly impacted MSC-mediated angiogenesis and cell migration. Further studies showed that SENP1 knockdown also suppressed the expression of a chemokine receptor CXCR4, and overexpression of CXCR4 could partially abrogate MRTF-A SUMOylation and reestablish the CCN1 level. Mutation analysis confirmed that SUMOylation occurred on three lysine residues (Lys-499, Lys-576, and Lys-624) of MRTF-A. In addition, SENP1 knockdown abolished the synergistic co-activation of CCN1 between MRTF-A and histone acetyltransferase p300 by suppressing acetylation on histone3K9, histone3K14, and histone4. These results revealed an important signaling pathway to regulate MSC differentiation and angiogenesis by MRTF-A SUMOylation involving cytokine/chemokine activities mediated by CCN1 and CXCR4, which may potentially impact a variety of cellular processes such as revascularization, wound healing, and progression of cancer.

| S-EPMC10046070 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data