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| Home > Publications database > Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma. |
| Home > Publications database > Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma. |
| Journal Article | DKFZ-2025-01397 |
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2025
Springer Nature
[London]
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Please use a persistent id in citations: doi:10.1038/s41467-025-61725-x
Abstract: Many cancers are defined by gene fusions that frequently encode oncogenic transcription factors (TFs), such as EWSR1::FLI1 in Ewing sarcoma (EwS). Here, we report that independently to its canonical roles in transcription, EWSR1::FLI1 also functions as an mRNA decay factor, reshaping mRNA stability in EwS. This function participates in EWSR1::FLI1 tumorigenicity and involves interactions of EWSR1::FLI1 with the CCR4-NOT deadenylation complex via its EWSR1-derived low-complexity domain and with the RNA-binding protein HuR/ELAVL1 via its FLI1-derived region. Strikingly, we find that EWSR1::FLI1-mediated mRNA decay antagonizes the normal mRNA protective function of HuR and renders EwS cells highly sensitive to HuR inhibition. Our findings uncover a post-transcriptional function of EWSR1::FLI1 and suggest that targeting mRNA stability mechanisms may offer therapeutic opportunities for EwS.
Keyword(s): Sarcoma, Ewing: genetics (MeSH) ; Sarcoma, Ewing: metabolism (MeSH) ; Sarcoma, Ewing: pathology (MeSH) ; Humans (MeSH) ; Proto-Oncogene Protein c-fli-1: metabolism (MeSH) ; Proto-Oncogene Protein c-fli-1: genetics (MeSH) ; RNA Stability: genetics (MeSH) ; RNA-Binding Protein EWS: metabolism (MeSH) ; RNA-Binding Protein EWS: genetics (MeSH) ; Cell Line, Tumor (MeSH) ; Animals (MeSH) ; Oncogene Proteins, Fusion: metabolism (MeSH) ; Oncogene Proteins, Fusion: genetics (MeSH) ; Mice (MeSH) ; RNA, Messenger: metabolism (MeSH) ; RNA, Messenger: genetics (MeSH) ; RNA-Binding Proteins: metabolism (MeSH) ; RNA-Binding Proteins: genetics (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Bone Neoplasms: genetics (MeSH) ; Bone Neoplasms: metabolism (MeSH) ; Proto-Oncogene Protein c-fli-1 ; EWSR1 protein, human ; RNA-Binding Protein EWS ; FLI1 protein, human ; Oncogene Proteins, Fusion ; RNA, Messenger ; RNA-Binding Proteins
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