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RING1B recruits EWSR1-FLI1 and cooperates in the remodelling of chromatin necessary for Ewing sarcoma tumorigenesis [microarray]

ABSTRACT: EWSR1-FLI1 genome reprogramming through remodeling of enhancers is determinant for Ewing sarcoma (ES) tumorigenesis. We describe a non-canonical function of RING1B, a PRC1 subunit highly expressed in primary ES tumors, co-localizing genome wide with EWSR1-FLI1 in active enhancers. While retaining its repressive canonical activity, we find RING1B as necessary for the expression of key EWSR1-FLI1 activated targets like NKX2-2, SOX2 or IGF1 where it mainly exerts a role in promoting oncogene recruitment to enhancers. Knockdown of RING1B is sufficient to impair growth of tumor xenografts and expression of EWSR1-FLI1 induced neomorphic enhancers in vivo. Restoration of RING1B ubiquitin ligase activity by the AURKB inhibitor AZD1152 decreases expression of RING1B/EWSR1-FLI1 common targets. Overall, our findings demonstrate RING1B as a critical modulator of EWSR1-FLI1 induced chromatin remodeling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133425 | GEO | 2020/10/27

REPOSITORIES: GEO

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RING1B recruits EWSR1-FLI1 and cooperates in the remodelling of chromatin necessary for Ewing sarcoma tumorigenesis [ChIP-Seq]

Project description:EWSR1-FLI1 genome reprogramming through remodeling of enhancers is determinant for Ewing sarcoma (ES) tumorigenesis. We describe a non-canonical function of RING1B, a PRC1 subunit highly expressed in primary ES tumors, co-localizing genome wide with EWSR1-FLI1 in active enhancers. While retaining its repressive canonical activity, we find RING1B as necessary for the expression of key EWSR1-FLI1 activated targets like NKX2-2, SOX2 or IGF1 where it mainly exerts a role in promoting oncogene recruitment to enhancers. Knockdown of RING1B is sufficient to impair growth of tumor xenografts and expression of EWSR1-FLI1 induced neomorphic enhancers in vivo. Restoration of RING1B ubiquitin ligase activity by the AURKB inhibitor AZD1152 decreases expression of RING1B/EWSR1-FLI1 common targets. Overall, our findings demonstrate RING1B as a critical modulator of EWSR1-FLI1 induced chromatin remodeling.

2020-10-27 | GSE131286 | GEO

LFQMS of RING2 (RING1B, RNF2) immunoprecipitation from MDA-MB-231 and T47D breast cancer cells

Project description:Polycomb repressive complex PRC1 is essential for gene regulation in numerous cell fate decisions. We show that RING1B (RING2, RNF2) and canonical PRC1 (cPRC1) genes are amplified and overexpressed in breast cancer (BC). Moreover, cPRC1 complexes functionally associate with genes regulated by cell type specific key transcription factors such as estrogen receptor (ER) in ER+ tumor cells and BRD4 in triple negative BC cells. cPRC1 is recruited to active enhancers in a manner independent of PRC2 and RING1B enzymatic activity. RING1B regulates enhancer activity and gene transcription not only by promoting the expression of BC oncogenes but also by regulating chromatin accessibility for oncogenic transcription factors. RING1B recruitment, and thus PRC1 association, to active enhancers occurs in multiple cancers.

2018-10-19 | PXD009570 | Pride

The PRC1 protein RING1B contributes to Ewing sarcoma tumorigenesis by repressing the NaV1.6 sodium channel and modulating the NF-kB pathway, independently of the fusion oncoprotein.

Project description:Ewing sarcoma (ES) is an aggressive tumor molecularly defined by reciprocal translocations of EWSR1 to an ETS transcription factor. The functions of EZH2 and BMI1, two proteins of the Polycomb group (PcG) of epigenetic repressors, have been previously shown to mediate specific features in EWSR1/ETS-transformed cells. Here we have characterized the expression and function of RING1B, a PcG protein with unique abilities, in ES. RING1B is highly and universally expressed in primary ES tumors. In contrast to EZH2, RING1B expression is independent of both the oncogene and of differentiation agents. RING1B depletion affects heme biosynthesis and hematopoiesis but does not result in a widespread alteration in ES differentiation. Among the unique set of genes regulated upon RING1B depletion, FGF14 and SCN8A, interacting components of the NaV1.6 channel, are two of the most up-regulated genes. Control of FGF14 and SCN8A in ES is specific of RING1B and functionally relevant. The signaling pathway most significantly modulated by RING1B is NF-κB. Indeed, RING1B depletion results in enhanced p105/p50 expression, which specifically sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. In conclusion, we show that RING1B is pivotal in ES cells, independently of the fusion oncogene, likely reflecting essential functional traits of the cell-of-origin.

2016-06-30 | GSE71007 | GEO

RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis [RNA-seq]

Project description:RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis [RNA-seq]

| PRJNA669990 | ENA

The PRC1 protein RING1B contributes to Ewing sarcoma tumorigenesis by repressing the NaV1.6 sodium channel and modulating the NF-kB pathway, independently of the fusion oncoprotein.

Project description:Ewing sarcoma (ES) is an aggressive tumor molecularly defined by reciprocal translocations of EWSR1 to an ETS transcription factor. The functions of EZH2 and BMI1, two proteins of the Polycomb group (PcG) of epigenetic repressors, have been previously shown to mediate specific features in EWSR1/ETS-transformed cells. Here we have characterized the expression and function of RING1B, a PcG protein with unique abilities, in ES. RING1B is highly and universally expressed in primary ES tumors. In contrast to EZH2, RING1B expression is independent of both the oncogene and of differentiation agents. RING1B depletion affects heme biosynthesis and hematopoiesis but does not result in a widespread alteration in ES differentiation. Among the unique set of genes regulated upon RING1B depletion, FGF14 and SCN8A, interacting components of the NaV1.6 channel, are two of the most up-regulated genes. Control of FGF14 and SCN8A in ES is specific of RING1B and functionally relevant. The signaling pathway most significantly modulated by RING1B is NF-ÎºB. Indeed, RING1B depletion results in enhanced p105/p50 expression, which specifically sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. In conclusion, we show that RING1B is pivotal in ES cells, independently of the fusion oncogene, likely reflecting essential functional traits of the cell-of-origin. 10 samples were analyzed: A4573 transduced with control shRNA; A4573 transduced with shRING1B; A673 transduced with control shRNA; A673 transduced with shRING1B; SK-ES-1 transduced with control shRNA; SK-ES-1 transduced with shRING1B; TC71 transduced with control shRNA; TC71 transduced with shRING1B; A673 transduced with shBMI1; TC71 transduced with shBMI1

2016-06-30 | E-GEOD-71007 | biostudies-arrayexpress

Gene expression profiling of human Ewing sarcoma cells after knockdown of EGR2 or EWSR1-FLI1.

Project description:To get insight in the functional role of EGR2 for Ewing sarcoma, we performed a transcriptional profiling of Ewing sarcoma cells after knockdown of EGR2 and compared the resulting transcriptional signature with that of EWSR1-FLI1-silenced Ewing sarcoma cells. In accordance with the strong EGR2-induction by EWSR1-FLI1, both genes highly significantly overlap in their transcriptional signatures. Gene-set enrichment analyses (GSEA) and DAVID (Database for Annotation, Visualisation and Integrated Discovery) gene ontology analyses indicated a strong impact of EGR2 on cholesterol and lipid biosynthesis resembling its function in orchestrating lipid metabolism of myelinating Schwann cells. A673 and SK-N-MC Ewing sarcoma cells were transfected with specific siRNAs directed against EGR2 or EWSR1-FLI1 or non-targeting control siRNA. 48 h thereafter RNA was harvested and processed for microarray analysis.

2015-07-26 | E-GEOD-62090 | biostudies-arrayexpress

Knowk-down of EWSR1-FLI1 in Ewing sarcoma cell lines (RNA-seq)

Project description:EWSR1-FLI1 is a chimeric transcription factor resulting from the pathognomonic translocation present in Ewing sarcoma cells. Here, we silenced EWSR1-FLI1 in different Ewing sarcoma cell lines. RNA from SKNMC, TC71 and MHH-ES1 cells was extracted 96h post transfection (siCT or siEWSR1-FLI1) or prior doxycycline (day 0) and 7 days after inducing silencing of EWSR1-FLI1 with doxycycline in ASP14 cells. RNA-seq was performed for all conditions.

2022-05-09 | GSE164372 | GEO

Gene expression profile upon EWSR1::FLI1 knockdown in Ewing sarcoma cells A673 in vitro

Project description:Ewing sarcoma, a rare and aggressive pediatric cancer, is characterized by chromosomal translocations that give rise to chimeric transcription factors. The most frequent of these chromosomal translocations is the t(11;22) that produces the fusion of the EWSR1 and FLI1 genes to generate the chimeric transcription factor EWSR1::FLI1. EWSR1::FLI1 is the main oncogenic event in Ewing's sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels may fluctuate in Ewing sarcoma cells, giving rise to two cell populations: cells expressing low levels of EWSR1::FLI1 are characterized by a more migratory and invasive phenotype, while cells expressing high levels of EWSR1::FLI1 are more proliferative. The identification and functional characterization of EWSR1::FLI1 gene targets is therefore relevant to understanding the pathobiology of Ewing sarcoma, which in turn could contribute to the identification of new therapeutic targets. Using this approach, we have observed that CD44, a transmembrane protein involved in cell adhesion and migration and associated with metastasis in various cancer types, is overexpressed in the EWSR1::FLI1-low phenotype. Our results suggest that CD44 may play a role in regulating cell migration in Ewing sarcoma cells and thus contribute to the spread of tumor cells.

2023-07-25 | GSE232739 | GEO

RING1B recruits EWSR1-FLI1 and cooperates in the remodelling of chromatin necessary for Ewing sarcoma tumorigenesis

Project description:RING1B recruits EWSR1-FLI1 and cooperates in the remodelling of chromatin necessary for Ewing sarcoma tumorigenesis

| PRJNA551441 | ENA

EWSR1::FLI1 fusion oncoproteins’ regulation of ETS1 (RNA-seq)

Project description:Ewing sarcomas harbor few mutations beyond the chromosomal translocation that initiates disease and the mechanistic basis for the metastasis of these tumors remains poorly understood. The epigenome of Ewing sarcoma (EWS) cells reflects the regulatory state of genes associated with the DNA binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the repressive activities of the EWSR1::FLI1/ERG fusion oncoproteins. Focusing on one of the repressed EWSR1::FLI1/ERG target genes, ETS1, we detected EWSR1::FLI1 binding and a H3K27me3 repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, and we show ETS1 regulates the expression of multiple proteins that function in extracellular matrix organization including TENSIN3 (TSN3). Interestingly, TSN3 expression in EWS tumors significantly correlates with that of ETS1 (0.85, FDR <0.01). TNS3 is a focal adhesion protein that contributes to tumor cell migration by connecting the cytoplasmic tail of integrins to the actin cytoskeleton. EWS cell lines, in which we activated ETS1 expression (CRISPRa) exhibited increased TNS3 expression and a migratory phenotype. Critically, the activated ETS1 EWS cell lines show TNS3 accumulation at leading cell edges, with F-actin cytoskeletal reorganization, a phenotype associated with cell migration.

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