TY  - JOUR
AU  - Galvan, Bartimée
AU  - Ongena, Loïc
AU  - Bruyr, Jonathan
AU  - Fettweis, Gregory
AU  - Lucarelli, Eva
AU  - Lavergne, Arnaud
AU  - Mariavelle, Emeline
AU  - O'Grady, Tina M
AU  - Hassoun, Zahrat El Oula
AU  - Claes, Margaux
AU  - Dubois, Laurence
AU  - Lee, Kevin A W
AU  - Kruys, Véronique
AU  - Gueydan, Cyril
AU  - Durand, Jules
AU  - Hervouet, Eric
AU  - Geyer, Florian
AU  - Banito, Ana
AU  - Imle, Roland
AU  - Mao, Lianghao
AU  - Jayavelu, Ashok K
AU  - Grünewald, Thomas
AU  - Cidre-Aranaz, Florencia
AU  - Twizere, Jean-Claude
AU  - Dequiedt, Franck
TI  - Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-01397
SP  - 6537
PY  - 2025
AB  - 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.
KW  - Sarcoma, Ewing: genetics
KW  - Sarcoma, Ewing: metabolism
KW  - Sarcoma, Ewing: pathology
KW  - Humans
KW  - Proto-Oncogene Protein c-fli-1: metabolism
KW  - Proto-Oncogene Protein c-fli-1: genetics
KW  - RNA Stability: genetics
KW  - RNA-Binding Protein EWS: metabolism
KW  - RNA-Binding Protein EWS: genetics
KW  - Cell Line, Tumor
KW  - Animals
KW  - Oncogene Proteins, Fusion: metabolism
KW  - Oncogene Proteins, Fusion: genetics
KW  - Mice
KW  - RNA, Messenger: metabolism
KW  - RNA, Messenger: genetics
KW  - RNA-Binding Proteins: metabolism
KW  - RNA-Binding Proteins: genetics
KW  - Gene Expression Regulation, Neoplastic
KW  - Bone Neoplasms: genetics
KW  - Bone Neoplasms: metabolism
KW  - Proto-Oncogene Protein c-fli-1 (NLM Chemicals)
KW  - EWSR1 protein, human (NLM Chemicals)
KW  - RNA-Binding Protein EWS (NLM Chemicals)
KW  - FLI1 protein, human (NLM Chemicals)
KW  - Oncogene Proteins, Fusion (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - RNA-Binding Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40664627
C2  - pmc:PMC12263829
DO  - DOI:10.1038/s41467-025-61725-x
UR  - https://inrepo02.dkfz.de/record/302857
ER  -