ArticleOncogene2021
The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct and separable from its DNA-binding function in Ewing sarcoma.
Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 39 citations in OpenAlex.
- Fusion Oncoprotein EWSR1::FLI1 Invades Nucleosomes at Consensus ETS Motifs and GGAA Microsatellites.bioRxiv : the preprint server for biology · 2026Article
- Article
- Proteomic landscape of Ewing sarcoma primary tumors and metastases.Nature communications · 2026Article
- LSD1 Performs Demethylase-Independent and Context-Specific Roles in Ewing Sarcoma.Cancer research communications · 2026Article
- Suppressing the Aberrant Transcriptional Functionality of EWS::FLI1 Oncoprotein by Designer polyQ Fusions with Its Homologous Peptides.Biomedicines · 2026Article
- LSD1 Performs Demethylase-Independent and Context-Specific Roles in Ewing Sarcoma.bioRxiv : the preprint server for biology · 2025Article
- A Novel FLI1 Monoclonal Antibody Which Recognizes EWS::FLI1 with High Affinity Is Useful for Detecting Ewing Sarcoma.Antibodies (Basel, Switzerland) · 2025Article
- FLI1 Expression in Invasive Breast Carcinoma: Clinicopathological Correlations and Prognostic Implications.Genes · 2025Article
- Molecular basis of EWS interdomain self-association and its role in condensate formation.Protein science : a publication of the Protein Society · 2025Article
- Seclidemstat (SP-2577) Induces Transcriptomic Reprogramming and Cytotoxicity in Multiple Fusion-Positive Sarcomas.Cancer research communications · 2025Article
- Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma.Nature communications · 2025Article
- Phase separation of the oncogenic fusion protein EWS::FLI1 is modulated by its DNA-binding domain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites.Nucleic acids research · 2025Article
- Endogenous EWSR1-FLI1 degron alleles enable control of fusion oncoprotein expression in tumor cell lines and xenografts.bioRxiv : the preprint server for biology · 2024Article
- Seclidemstat blocks the transcriptional function of multiple FET-fusion oncoproteins.bioRxiv : the preprint server for biology · 2024Article
- 3C methods in cancer research: recent advances and future prospects.Experimental & molecular medicine · 2024Review
- USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma.Molecular cancer research : MCR · 2023Article
- Biochemical and biophysical characterization of the nucleic acid binding properties of the RNA/DNA binding protein EWS.Biopolymers · 2023Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Ewing sarcoma is an aggressive bone cancer of children and young adults defined by the presence of a chromosomal translocation: t(11;22)(q24;q12). The encoded protein, EWS/FLI, fuses the amino-terminal domain of EWS to the carboxyl-terminus of FLI. The EWS portion is an intrinsically disordered transcriptional regulatory domain, while the FLI portion contains an ETS DNA-binding domain and two flanking regions of unknown function. Early studies using non-Ewing sarcoma models provided conflicting information on the roles of each domain of FLI in EWS/FLI oncogenic function. We therefore sought to define the specific contributions of each FLI domain to EWS/FLI activity in a well-validated Ewing sarcoma model and, in doing so, to better understand Ewing sarcoma development mediated by the fusion protein. We analyzed a series of engineered EWS/FLI mutants with alterations in the FLI portion using a variety of assays. Fluorescence anisotropy, CUT&RUN, and ATAC-sequencing experiments revealed that the isolated ETS domain is sufficient to maintain the normal DNA-binding and chromatin accessibility function of EWS/FLI. In contrast, RNA-sequencing and soft agar colony formation assays revealed that the ETS domain alone was insufficient for transcriptional regulatory and oncogenic transformation functions of the fusion protein. We found that an additional alpha-helix immediately downstream of the ETS domain is required for full transcriptional regulation and EWS/FLI-mediated oncogenesis. These data demonstrate a previously unknown role for FLI in transcriptional regulation that is distinct from its DNA-binding activity. This activity is critical for the cancer-causing function of EWS/FLI and may lead to novel therapeutic approaches.
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