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Gene expression in Ewing tumor cell lines after STEAP1 silencing

ABSTRACT: Goal: identification of differentially expressed genes after STEAP1 silencing. Ewing tumors (ET) are characterized by oncogenic EWS/ETS translocations and early metastasis. STEAP1 is a membrane-bound channel protein of unkown function. While overexpressed in many cancers, STEAP1 expression is strongly restricted to mesenchymal stem cells, prostate and urothelium among benign tissues. Here we show that STEAP1 is a direct transcriptional target of EWS/FLI1 and critical for ET malignancy. We demonstrate that STEAP1 is most prominently expressed in ET among sarcomas and provide further evidence for the concept of STEAP1 as a universal diagnostic marker for carcinomas. Using RNA interference we determined that STEAP1 promotes cellular invasiveness and anchorage-independent growth in vitro and accelerates tumor growth and metastasis in vivo. Transcriptome and proteome analyses as well as functional studies reveal that STEAP1 contributes to the generation of reactive oxygen species that in turn regulate the levels of redox-sensitive signaling molecules and pro-metatstatic genes. In synopsis, these data illuminate the hitherto unkown oncogenic function of STEAP1 as a redox-modulator in ET and point to a potential role of STEAP1 as universal drug target for anti-cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26422 | GEO | 2012/01/01

SECONDARY ACCESSION(S): PRJNA136799

REPOSITORIES: GEO

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Gene expression in Ewing tumor cell lines after STEAP1 silencing

Project description:Goal: identification of differentially expressed genes after STEAP1 silencing. Ewing tumors (ET) are characterized by oncogenic EWS/ETS translocations and early metastasis. STEAP1 is a membrane-bound channel protein of unkown function. While overexpressed in many cancers, STEAP1 expression is strongly restricted to mesenchymal stem cells, prostate and urothelium among benign tissues. Here we show that STEAP1 is a direct transcriptional target of EWS/FLI1 and critical for ET malignancy. We demonstrate that STEAP1 is most prominently expressed in ET among sarcomas and provide further evidence for the concept of STEAP1 as a universal diagnostic marker for carcinomas. Using RNA interference we determined that STEAP1 promotes cellular invasiveness and anchorage-independent growth in vitro and accelerates tumor growth and metastasis in vivo. Transcriptome and proteome analyses as well as functional studies reveal that STEAP1 contributes to the generation of reactive oxygen species that in turn regulate the levels of redox-sensitive signaling molecules and pro-metatstatic genes. In synopsis, these data illuminate the hitherto unkown oncogenic function of STEAP1 as a redox-modulator in ET and point to a potential role of STEAP1 as universal drug target for anti-cancer therapy. 6 samples (3x A673 cells; 3x SK-N-MC cells); for each cell line one sample was transfected with control non silencing siRNA and two samples with different STEAP1 siRNAs (siSTEAP1_2 and siSTEAP1_3).

2012-01-01 | E-GEOD-26422 | biostudies-arrayexpress

c-Myc targeted genes validated by PCR array in STEAP1-silenced HepG2 cells.

Project description:To confirm the relationship between STEAP1 and c-Myc in liver cancer, we analyzed components of c-Myc-related genes after STEAP1 knockdown in HepG2 cells by PCR array.

2021-05-05 | GSE173813 | GEO

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy [TCR-seq]

Project description:Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. Here, we identified broad expression of STEAP1 relative to the established theranostic target prostate-specific membrane antigen (PSMA) in a series of lethal metastatic prostate cancers which prompted the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrated reactivity in low antigen density, antitumor activity across multiple metastatic human and mouse prostate cancer models, and preliminary safety in a human STEAP1 knock-in mouse model. In human-in-mouse and mouse-in-mouse studies, STEAP1 CAR T cell therapy yielded effective tumor responses, but antigen escape was appreciated as a recurrent mechanism of treatment resistance and STEAP1 antigen loss was associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein as an adjunct to STEAP1 CAR T cell therapy enhanced antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading. In summary, we describe the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, characterize a STEAP1 CAR T cell therapy with preclinical evidence of potency and safety, and nominate a combinatorial immunotherapy strategy to overcome barriers to the efficacy of CAR T cell therapy in advanced prostate cancer.

2023-04-03 | GSE228884 | GEO

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy [scRNA-seq]

2023-03-22 | GSE214584 | GEO

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy [bulk RNA-seq]

2023-03-22 | GSE214583 | GEO

Quantitative Proteome Analysis reveal the involvement of STEAP1 on vesicles-mediated transport in human LNCaP prostate cancer cells

Project description:Prostate cancer (PCa) continues to be one of the most common cancers in men worldwide. The six transmembrane epithelial antigen of the prostate 1 (STEAP1) protein is overexpressed in several types of human tumours, particularly in PCa. Our research group has demonstrated that STEAP1 overexpression is associated with PCa progression and aggressiveness. Therefore, understanding the cellular and molecular mechanisms triggered by STEAP1 overexpression will provide important insights to delineate new strategies for PCa treatment. In the present work, a proteomic strategy was used to characterize the intracellular signalling pathways and the molecular targets downstream of STEAP1 in PCa cells. A label-free approach was applied using an Orbitrap LC-MS/MS system to characterize the proteome of STEAP1-knockdown PCa cells. More than 6700 proteins were identified, of which a total of 526 proteins were found differentially expressed in scramble siRNA versus STEAP1 siRNA (234 proteins up-regulated and 292 proteins down-regulated). Bioinformatics analysis allowed us to explore the mechanism through which STEAP1 exerts influence on PCa, revelling that endocytosis, RNA transport, apoptosis, aminoacyl-tRNA biosynthesis and metabolic pathways are the biological processes where STEAP1 is involved. By immunoblotting, it was confirmed that STEAP1 knockdown induced the up-regulation of cathepsin B, intersectin-1 and syntaxin 4,while it down-regulation HRas, PIK3C2A and DIS3. These finding suggested that blocking STEAP1 might be a strategy to activate apoptosis and endocytosis, and diminish cellular metabolism and intercellular communication, leading to inhibition of PCa progression.

2023-10-18 | PXD037834 | Pride

IL1RAP augments cysteine metabolism to promote ferroptosis resistance and metastasis in Ewing sarcoma

Project description:Aggressive cancer cells must adapt and overcome oxidative stress encountered during the metastatic cascade to successfully disseminate. In this work, a combination of proteomic approaches is used to identify the IL1 receptor accessory protein (IL1RAP) as an in vitro suppressor of anoikis (detachment-induced cell death). IL1RAP is found to be a direct transcriptional target of characteristic Ewing sarcoma (EwS) oncogenic fusions and an important overall mediator of redox homeostasis through the maintenance of glutathione (GSH) synthesis. IL1RAP is found to control intracellular cysteine and GSH synthesis in EwS via binding to CD98 and SLC7A11 of the system Xc- transporter to enhance exogenous cystine uptake for cysteine conversion. In addition, IL1RAP transcriptionally controls cystathionine gamma lyase (CTH), an enzyme that is crucial for de novo cysteine synthesis via the transsulfuration pathway. IL1RAP or CTH depletion is found to susceptibility to ferroptosis and dramatically reduced overall lung metastasis of EwS xenografts in mice. Together, this work describes the critical role of IL1RAP in the maintenance of redox homeostasis through cysteine metabolism in EwS, and identifies a previously unidentified pathway in the pathobiology of this disease.

2021-05-25 | PXD019009 | Pride

EZH2 is a mediator of EWS-FLI1 driven tumor growth blocking endothelial and neuro-ectodermal differentiation

Project description:Ewing Tumors (ET) are highly malignant tumors, localized in bone or soft tissue and are molecularly defined by ews/ets translocations. We identified histone methyl-transferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. EZH2’s suppressive activity maintains stemness in normal and malignant cells. Here we found EZH2 to be upregulated by the pathognomonic fusion oncogene EWS-FLI1 in ET and mesenchymal stem cells. Downregulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis in immunodeficient Rag2-/-γC-/- mice was suppressed. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. Downregulation of EZH2 decreased histone H3 lysine 27 trimethylation (H3K27me3) at target loci. EZH2 regulated stemness genes such as nerve growth factor receptor (NGFR) as well as genes involved in neuroectodermal differentiation (EMP1, EPHB2, GFAP, GAP43). These data suggest that EZH2 might play a central role in Ewing Tumor pathology shaping the oncogenicity and stem cell phenotype of this tumor presumably by epigenetic regulation.

2008-10-01 | GSE12692 | GEO

RNAi profiling of human ezh2 specific siRNA A673 treated cells reveals EZh2 is a mediator of EWS-FLI1 driven tumor growth blocking endothelial and neuro-ectodermal differentiation

Project description:Ewing Tumors (ET) are highly malignant tumors, localized in bone or soft tissue and are molecularly defined by ews/ets translocations. We identified histone methyl-transferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. EZH2âs suppressive activity maintains stemness in normal and malignant cells. Here we found EZH2 to be upregulated by the pathognomonic fusion oncogene EWS-FLI1 in ET and mesenchymal stem cells. Downregulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis in immunodeficient Rag2-/-Î³C-/- mice was suppressed. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. Downregulation of EZH2 decreased histone H3 lysine 27 trimethylation (H3K27me3) at target loci. EZH2 regulated stemness genes such as nerve growth factor receptor (NGFR) as well as genes involved in neuroectodermal differentiation (EMP1, EPHB2, GFAP, GAP43). These data suggest that EZH2 might play a central role in Ewing Tumor pathology shaping the oncogenicity and stem cell phenotype of this tumor presumably by epigenetic regulation. Experiment Overall Design: A673 cells were treated for 24 hours either with 100 nM Trichostatin A (TSA) or 0.01% DMSO. In siRNA experiments with ezh2 specific siRNA A673 cells were resuspended in medium containing 5 nM siRNA and transfection reagent and incubated for 48 hours. RNA from cells under such treatment was isolated with Trizol and subjected to microarray analysis onto human U133A microarray following the Affymetrix protocol.

2008-10-26 | E-GEOD-12692 | biostudies-arrayexpress

Targeting the EWS/ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma

Project description:Ewing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by early metastasis into lung and bone. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS/FLI1 in a dose dependent manner. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program could be mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS/FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program in ES. Ewing sarcoma cell lines A673 and TC-71 were treated for 48 hours with 2 microM JQ1 or DMSO control.

2015-12-08 | E-GEOD-72673 | biostudies-arrayexpress

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