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@ARTICLE{Galvan:302857,
author = {B. Galvan and L. Ongena and J. Bruyr and G. Fettweis and E.
Lucarelli and A. Lavergne and E. Mariavelle and T. M.
O'Grady and Z. E. O. Hassoun and M. Claes and L. Dubois and
K. A. W. Lee and V. Kruys and C. Gueydan and J. Durand and
E. Hervouet and F. Geyer$^*$ and A. Banito$^*$ and R.
Imle$^*$ and L. Mao and A. K. Jayavelu and T. Grünewald$^*$
and F. Cidre-Aranaz$^*$ and J.-C. Twizere and F. Dequiedt},
title = {{S}ubversion of m{RNA} degradation pathways by
{EWSR}1::{FLI}1 represents a therapeutic vulnerability in
{E}wing sarcoma.},
journal = {Nature Communications},
volume = {16},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {DKFZ-2025-01397},
pages = {6537},
year = {2025},
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.},
keywords = {Sarcoma, Ewing: genetics / Sarcoma, Ewing: metabolism /
Sarcoma, Ewing: pathology / Humans / Proto-Oncogene Protein
c-fli-1: metabolism / Proto-Oncogene Protein c-fli-1:
genetics / RNA Stability: genetics / RNA-Binding Protein
EWS: metabolism / RNA-Binding Protein EWS: genetics / Cell
Line, Tumor / Animals / Oncogene Proteins, Fusion:
metabolism / Oncogene Proteins, Fusion: genetics / Mice /
RNA, Messenger: metabolism / RNA, Messenger: genetics /
RNA-Binding Proteins: metabolism / RNA-Binding Proteins:
genetics / Gene Expression Regulation, Neoplastic / Bone
Neoplasms: genetics / Bone Neoplasms: metabolism /
Proto-Oncogene Protein c-fli-1 (NLM Chemicals) / EWSR1
protein, human (NLM Chemicals) / RNA-Binding Protein EWS
(NLM Chemicals) / FLI1 protein, human (NLM Chemicals) /
Oncogene Proteins, Fusion (NLM Chemicals) / RNA, Messenger
(NLM Chemicals) / RNA-Binding Proteins (NLM Chemicals)},
cin = {B410 / HD01 / B380},
ddc = {500},
cid = {I:(DE-He78)B410-20160331 / I:(DE-He78)HD01-20160331 /
I:(DE-He78)B380-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40664627},
pmc = {pmc:PMC12263829},
doi = {10.1038/s41467-025-61725-x},
url = {https://inrepo02.dkfz.de/record/302857},
}