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

ABSTRACT: Analysis of differential expression profiles of tumors wild-type and RING1B knock-down

ORGANISM(S): Homo sapiens

PROVIDER: GSE159525 | GEO | 2020/10/27

REPOSITORIES: GEO

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

Project description:Ewing sarcoma (EwS) is an aggressive tumor that affects adolescents and young adults. EwS is defined by a chromosomal translocation, EWSR1-FLI1 being the most common, that causes genome reprogramming through remodeling of enhancers. Here, we describe an unexpected function of RING1B, which is highly expressed in EwS. While retaining its repressive activity at Polycomb developmental regulated genes, RING1B colocalizes with EWSR1-FLI1 at active enhancers. We demonstrate that RING1B is necessary for the expression of key EWSR1-FLI1 targets by facilitating oncogene recruitment to their enhancers. Knockdown of RING1B impairs growth of tumor xenografts and expression of genes regulated by EWSR1-FLI1 bound enhancers. Pharmacological inhibition of AURKB with AZD1152 increases H2Aub levels causing down-regulation of RING1B/EWSR1-FLI1 common targets. Our findings demonstrate that RING1B is a critical modulator of EWSR1-FLI1-induced chromatin remodeling, and its inhibition is a potential therapeutic strategy for the treatment of these tumors.

| S-EPMC7608835 | biostudies-literature

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

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 | GSE133425 | GEO

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

2020-10-27 | GSE131286 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-27 | GSE133427 | 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

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

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

| PRJNA551438 | ENA

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

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

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

| PRJNA543121 | ENA

High Specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG Positive Ewing Sarcoma.

Project description:Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for EWSR1-FLI1-positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including EWSR1-ERG-positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by EWSR1-ERG-positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available.

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Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma.

Project description:Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1-FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1-FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1-FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1-FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1-FLI1 at the cell level should be considered a therapeutic approach to develop in the future.

| S-EPMC8345183 | biostudies-literature

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