Proto-Oncogene Protein c-fli-1; EWSR1 protein, human; RNA-Binding Protein EWS; FLI1 protein, human; Oncogene Proteins, Fusion; RNA, Messenger; RNA-Binding Proteins; Humans; 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; Sarcoma, Ewing/genetics; Sarcoma, Ewing/metabolism; Sarcoma, Ewing/pathology; 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; Bone Neoplasms/genetics; Bone Neoplasms/metabolism
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Galvan, Bartimée ; Université de Liège - ULiège > GIGA ; Division of Oncology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland
Bruyr, Jonathan ; Université de Liège - ULiège > GIGA > GIGA Molecular & Computational Biology - Gene Expression & Cancer
Fettweis, Grégory ; Université de Liège - ULiège > Département des sciences de la vie ; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, USA
Lucarelli, Eva ; Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales
Lavergne, Arnaud ; Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA)
O'Grady, Tina M ; Laboratory of Gene Expression and Cancer, GIGA Institute, University of Liège (ULiège), Liège, Belgium ; Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, USA
Hassoun, Zahrat El Oula ; Université de Liège - ULiège > GIGA ; Department of Integrative Structural and Computational Biology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, USA
Lee, Kevin A W; Division of Life Science, The Hong Kong University of Sci. & Tech, Clear Water Bay, Kowloon, Hong Kong SAR, China
Kruys, Véronique; Laboratory of Molecular Biology of the Gene, Department of Molecular Biology, Free University of Brussels (ULB), 6041, Gosselies, Belgium
Gueydan, Cyril; Laboratory of Molecular Biology of the Gene, Department of Molecular Biology, Free University of Brussels (ULB), 6041, Gosselies, Belgium
Durand, Jules; Université Franche-Comté, INSERM, EFS BFC, UMR1098, « Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique », F-25000, Besançon, France ; EPIGENExp platform, Université Franche-Comté, F-25000, Besançon, France
Hervouet, Eric ; Université Franche-Comté, INSERM, EFS BFC, UMR1098, « Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique », F-25000, Besançon, France ; EPIGENExp platform, Université Franche-Comté, F-25000, Besançon, France
Geyer, Florian H; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany ; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
Banito, Ana ; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ; Soft-Tissue Sarcoma research group (B380), German Cancer Research Center (DKFZ), Heidelberg, Germany
Imle, Roland ; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ; Soft-Tissue Sarcoma research group (B380), German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
Mao, Lianghao; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany ; Research Group Proteomics and Cancer Cell Signaling, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Jayavelu, Ashok K ; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany ; Research Group Proteomics and Cancer Cell Signaling, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Grünewald, Thomas G P ; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany ; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany ; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Cidre-Aranaz, Florencia ; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany ; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany ; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
T.I. Lee R.A. Young Transcriptional regulation and its misregulation in disease Cell 152 1237 1251 1:CAS:528:DC%2BC3sXktFWiuro%3D 23498934 3640494
J.E. Bradner D. Hnisz R.A. Young Transcriptional addiction in Cancer Cell 168 629 643 1:CAS:528:DC%2BC2sXis1ygtbk%3D 28187285 5308559
L.A. Garraway E.S. Lander Lessons from the cancer genome Cell 153 17 37 1:CAS:528:DC%2BC3sXltVensb0%3D 23540688
V. Damerell M.S. Pepper S. Prince Molecular mechanisms underpinning sarcomas and implications for current and future therapy Signal Transduct. Target Ther. 6 246 1:CAS:528:DC%2BB3MXhsFait73J 34188019 8241855
J.A. Perry B.K.A. Seong K. Stegmaier Biology and therapy of dominant fusion oncoproteins involving transcription factor and chromatin regulators in sarcomas Annu Rev. Cancer Biol. 3 299 321
G.L. Brien K. Stegmaier S.A. Armstrong Targeting chromatin complexes in fusion protein-driven malignancies Nat. Rev. Cancer 19 255 269 1:CAS:528:DC%2BC1MXosVShurw%3D 30962549
O. Delattre et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours Nature 359 162 165 1992Natur.359.162D 1:CAS:528:DyaK3sXkvFantL0%3D 1522903
M. Patel et al. Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription Genome Res. 22 259 270 1:CAS:528:DC%2BC38XhsFygtr0%3D 22086061 3266033
K. Gangwal et al. Microsatellites as EWS/FLI response elements in Ewing’s sarcoma Proc. Natl. Acad. Sci. USA 105 10149 10154 2008PNAS.10510149G 1:CAS:528:DC%2BD1cXptF2rsb8%3D 18626011 2481306
E.M. Tomazou et al. Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1 Cell Rep. 10 1082 1095 1:CAS:528:DC%2BC2MXjtlSqtL4%3D 25704812 4542316
N.C. Sheffield et al. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma Nat. Med 23 386 395 1:CAS:528:DC%2BC2sXhvVaqt7g%3D 28134926 5951283
N. Riggi et al. EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma Cancer Cell 26 668 681 1:CAS:528:DC%2BC2cXhvVGks7bJ 25453903 4492343
Song, J., Ng, S. C., Tompa, P., Lee, K. A. W. & Chan, H. S. Polycation-π interactions are a driving force for molecular recognition by an intrinsically disordered oncoprotein family. PLoS Comput. Biol. 9, e1003239 (2013).
J. Vibert et al. Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions Mol. Cell 82 2458 2471.e9 1:CAS:528:DC%2BB38Xht1KmtbbJ 35550257
Barrett, C., Budhiraja, A., Parashar, V. & Batish, M. The landscape of regulatory noncoding RNAs in Ewing’s sarcoma. Biomedicines9, 933 (2021).
G. Boulay et al. Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies Genes Dev. 32 1008 1019 1:CAS:528:DC%2BC1cXitVWgtb7J 30042132 6075149
Li, M. & Chen, C.-W. Epigenetic and transcriptional signaling in Ewing sarcoma-disease etiology and therapeutic opportunities. Biomedicines10, 1325 (2022).
I.A. Showpnil et al. EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma Nucleic Acids Res. 50 9814 9837 1:CAS:528:DC%2BB3sXkslaqu7k%3D 36124657 9508825
Sanalkumar, R. et al. Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity. Sci. Adv.9, eabo3789 (2023).
K.A. Braun E.T. Young Coupling mRNA synthesis and decay Mol. Cell Biol. 34 4078 4087 25154419 4248707
G. Haimovich M. Choder R.H. Singer T. Trcek The fate of the messenger is pre-determined: a new model for regulation of gene expression Biochim. Biophys. Acta 1829 643 653 1:CAS:528:DC%2BC3sXitlaksL8%3D 23337853 3891481
E. Wahle G.S. Winkler RNA decay machines: deadenylation by the Ccr4-not and Pan2-Pan3 complexes Biochim. Biophys. Acta 1829 561 570 1:CAS:528:DC%2BC3sXjtVSjsLg%3D 23337855
T. Raisch et al. Reconstitution of recombinant human CCR4-NOT reveals molecular insights into regulated deadenylation Nat. Commun. 10 2019NatCo.10.3173R 31320642 6639331 3173
A. Sgromo et al. A CAF40-binding motif facilitates recruitment of the CCR4-NOT complex to mRNAs targeted by Drosophila Roquin Nat. Commun. 8 2017NatCo..814307S 1:CAS:528:DC%2BC2sXitlClurg%3D 28165457 5303829 14307
T. Raisch et al. Distinct modes of recruitment of the CCR4-NOT complex by Drosophila and vertebrate Nanos EMBO J. 35 974 990 1:CAS:528:DC%2BC28XktVOmtLw%3D 26968986 5207322
K. Leppek et al. Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs Cell 153 869 881 1:CAS:528:DC%2BC3sXnsFSkuro%3D 23663784
A.A. Sarshad et al. Argonaute-miRNA complexes silence target mRNAs in the nucleus of mammalian stem cells Mol. Cell 71 1040 1050.e8 1:CAS:528:DC%2BC1cXhsFyktbbE 30146314 6690358
J. Solana et al. The CCR4-NOT complex mediates deadenylation and degradation of stem cell mRNAs and promotes planarian stem cell differentiation PLoS Genet 9 e1004003 24367277 3868585
N. Battich et al. Sequencing metabolically labeled transcripts in single cells reveals mRNA turnover strategies Science 367 1151 1156 2020Sci..367.1151B 1:CAS:528:DC%2BB3cXktlOisLg%3D 32139547
Krenning, L., Sonneveld, S. & Tanenbaum, M. Time-resolved single-cell sequencing identifies multiple waves of mRNA decay during the mitosis-to-G1 phase transition. Elife11, e71356 (2022).
T. Akiyama T. Yamamoto Regulation of early lymphocyte development via mRNA decay catalyzed by the CCR4-not complex Front Immunol. 12 715675 1:CAS:528:DC%2BB3MXitFOhsrvM 34349771 8326961
G. Perron et al. Pan-cancer analysis of mRNA stability for decoding tumour post-transcriptional programs Commun. Biol. 5 851 1:CAS:528:DC%2BB38Xit1Ojtr%2FK 35987939 9392771
G. Perron et al. A general framework for interrogation of mRNA stability programs identifies RNA-binding proteins that govern cancer transcriptomes Cell Rep. 23 1639 1650 1:CAS:528:DC%2BC1cXptFCqsLw%3D 29742422
X. Rambout et al. The transcription factor ERG recruits CCR4-NOT to control mRNA decay and mitotic progression Nat. Struct. Mol. Biol. 23 663 672 1:CAS:528:DC%2BC28XpsVCku7s%3D 27273514
C.-Y. Yang et al. Interaction of CCR4-NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis Genes Dev. 30 2310 2324 1:CAS:528:DC%2BC2sXitV2lsrw%3D 27807034 5110997
A. Bertero et al. The SMAD2/3 interactome reveals that TGFβ controls m(6)A mRNA methylation in pluripotency Nature 555 256 259 2018Natur.555.256B 1:CAS:528:DC%2BC1cXjsFaitLY%3D 29489750 5951268
T. Song et al. Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation Nucleic Acids Res. 47 6130 6144 1:CAS:528:DC%2BB3cXisVCqsbo%3D 31037292 6614822
K.A. France J.L. Anderson A. Park C.T. Denny Oncogenic fusion protein EWS/FLI1 down-regulates gene expression by both transcriptional and posttranscriptional mechanisms J. Biol. Chem. 286 22750 22757 1:CAS:528:DC%2BC3MXnvFektb8%3D 21531709 3123042
F. Tirode et al. Mesenchymal stem cell features of Ewing tumors Cancer Cell 11 421 429 1:CAS:528:DC%2BD2sXlsVahu7c%3D 17482132
G.-A. Franzetti et al. Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells Oncogene 36 3505 3514 1:CAS:528:DC%2BC2sXhvVShsLs%3D 28135250 5541267
N. Riggi et al. EWS-FLI-1 expression triggers a Ewing’s sarcoma initiation program in primary human mesenchymal stem cells Cancer Res. 68 2176 2185 1:CAS:528:DC%2BD1cXktVyqurs%3D 18381423
M. Watson Y. Park C. Thoreen Roadblock-qPCR: A simple and inexpensive strategy for targeted measurements of mRNA stability RNA 27 335 342 33288682
D. Gaidatzis L. Burger M. Florescu M.B. Stadler Analysis of intronic and exonic reads in RNA-seq data characterizes transcriptional and post-transcriptional regulation Nat. Biotechnol. 33 722 729 1:CAS:528:DC%2BC2MXhtFait77J 26098447
R. Alkallas L. Fish H. Goodarzi H.S. Najafabadi Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer’s disease Nat. Commun. 8 2017NatCo..8.909A 29030541 5714957 909
Y. Luo Z. Na S.A. Slavoff P-Bodies: composition, properties, and functions Biochemistry 57 2424 2431 1:CAS:528:DC%2BC1cXhvVWksrY%3D 29381060
N. Standart D. Weil P-Bodies: Cytosolic droplets for coordinated mRNA storage Trends Genet. 34 612 626 1:CAS:528:DC%2BC1cXhtVKjtLfM 29908710
Tian, S., Curnutte, H. A. & Trcek, T. RNA granules: a view from the RNA perspective. Molecules25, 3130 (2020).
M. Kauer et al. A molecular function map of Ewing’s sarcoma PLoS ONE 4 e5415 2009PLoSO..4.5415K 19404404 2671847
M.F. Orth et al. Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation Cell Rep. 41 111761 1:CAS:528:DC%2BB38XjtVKksb7O 36476851 10333306
J. Houseley D. Tollervey The many pathways of RNA degradation Cell 136 763 776 1:CAS:528:DC%2BD1MXkvFGktr8%3D 19239894
J.-Y. Youn et al. Properties of stress granule and P-body proteomes Mol. Cell 76 286 294 1:CAS:528:DC%2BC1MXitVSls7nE 31626750
C. Barreau T. Watrin H. Beverley Osborne L. Paillard Protein expression is increased by a class III AU-rich element and tethered CUG-BP1 Biochem. Biophys. Res. Commun. 347 723 730 1:CAS:528:DC%2BD28Xntl2jtro%3D 16843434
Y.-B. Yan Deadenylation: enzymes, regulation, and functional implications Wiley Interdiscip. Rev. RNA 5 421 443 1:CAS:528:DC%2BC2cXmsFWntbw%3D 24523229
L.A. Passmore J. Coller Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression Nat. Rev. Mol. Cell Biol. 23 93 106 1:CAS:528:DC%2BB3MXitFGru7fE 34594027
Cassonnet, P. et al. Benchmarking a luciferase complementation assay for detecting protein complexes. Nat. Methods8, 990−992 (2011).
A. Boland et al. Structure and assembly of the NOT module of the human CCR4-NOT complex Nat. Struct. Mol. Biol. 20 1289 1297 1:CAS:528:DC%2BC3sXhs1SrtrnE 24121232
N.C. Lau et al. Human Ccr4-Not complexes contain variable deadenylase subunits Biochem. J. 422 443 453 1:CAS:528:DC%2BD1MXhtVygs7%2FI 19558367
M.A. Boone et al. The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct and separable from its DNA-binding function in Ewing sarcoma Oncogene 40 4759 4769 1:CAS:528:DC%2BB3MXhtlGlt7rP 34145397 8298202
K.P. Ng et al. Multiple aromatic side chains within a disordered structure are critical for transcription and transforming activity of EWS family oncoproteins Proc. Natl. Acad. Sci. USA 104 479 484 2007PNAS.104.479N 1:CAS:528:DC%2BD2sXptVCnsQ%3D%3D 17202261 1766410
K.A.W. Lee Molecular recognition by the EWS transcriptional activation domain Adv. Exp. Med. Biol. 725 106 125 1:CAS:528:DC%2BC38XhtlynsbvJ 22399321
D. Surdez et al. STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma Cancer Cell 39 810 826.e9 1:CAS:528:DC%2BB3MXhtVartbbK 33930311
W.A. May et al. Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation Proc. Natl. Acad. Sci. USA 90 5752 5756 1993PNAS..90.5752M 1:CAS:528:DyaK3sXltFCmsbw%3D 8516324 46800
S.M. Welford S.P. Hebert B. Deneen A. Arvand C.T. Denny DNA binding domain-independent pathways are involved in EWS/FLI1-mediated oncogenesis J. Biol. Chem. 276 41977 41984 1:CAS:528:DC%2BD3MXosVGntbw%3D 11553628
G. Boulay et al. Cancer-specific retargeting of BAF complexes by a prion-like domain Cell 171 163 178.e19 1:CAS:528:DC%2BC2sXhtlylsb%2FI 28844694 6791823
M. Kato et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels Cell 149 753 767 1:CAS:528:DC%2BC38XntFams7g%3D 22579281 6347373
D.M. Presman et al. DNA binding triggers tetramerization of the glucocorticoid receptor in live cells Proc. Natl. Acad. Sci. USA 113 8236 8241 2016PNAS.113.8236P 1:CAS:528:DC%2BC28XhtFensbbL 27382178 4961135
M.A. Digman R. Dalal A.F. Horwitz E. Gratton Mapping the number of molecules and brightness in the laser scanning microscope Biophys. J. 94 2320 2332 2008BpJ..94.2320D 1:CAS:528:DC%2BD1cXjtlKjsrw%3D 18096627
O. Saulnier et al. ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion Nucleic Acids Res. 49 5038 5056 1:CAS:528:DC%2BB3MXhs1WjurbN 34009296 8136815
L.L. Knoop S.J. Baker EWS/FLI alters 5’-splice site selection J. Biol. Chem. 276 22317 22322 1:CAS:528:DC%2BD3MXkvVanu7g%3D 11301318
S.P. Selvanathan et al. Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing Proc. Natl. Acad. Sci. USA 112 E1307 E1316 1:CAS:528:DC%2BC2MXjs1Khur8%3D 25737553 4371969
S.P. Selvanathan et al. EWS-FLI1 modulated alternative splicing of ARID1A reveals novel oncogenic function through the BAF complex Nucleic Acids Res. 47 9619 9636 1:CAS:528:DC%2BB3cXhtVSktrfJ 31392992 6765149
S. Sun Z. Zhang O. Fregoso A.R. Krainer Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2 RNA 18 274 283 1:CAS:528:DC%2BC38Xhs1ygs7g%3D 22184459 3264914
V.K. Mayya T.F. Duchaine Ciphers and executioners: how 3’-untranslated regions determine the fate of messenger RNAs Front Genet 10 6 1:CAS:528:DC%2BC1MXht1OltbnE 30740123 6357968
C. Barreau L. Paillard H.B. Osborne AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Res. 33 7138 7150 1:CAS:528:DC%2BD28XisFKqsA%3D%3D 16391004
N. Mukherjee et al. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability Mol. Cell 43 327 339 1:CAS:528:DC%2BC3MXpvFSqsLk%3D 21723170 3220597
V.G. D’Agostino et al. Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function Sci. Rep. 5 1 15
P. Lal et al. Regulation of HuR structure and function by dihydrotanshinone-I Nucleic Acids Res. 45 9514 9527 1:CAS:528:DC%2BC1cXmtV2gsb0%3D 28934484 5766160
Abdelmohsen, K. & Gorospe, M. Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA. 1, 214−229 (2010).
X. Wu et al. Identification and Validation of Novel Small Molecule Disruptors of HuR-mRNA Interaction ACS Chem. Biol. 10 1476 1484 1:CAS:528:DC%2BC2MXjvFyntL8%3D 25750985 4631057
E.R. Lawlor C. Scheel J. Irving P.H.B. Sorensen Anchorage-independent multi-cellular spheroids as an in vitro model of growth signaling in Ewing tumors Oncogene 21 307 318 1:CAS:528:DC%2BD38XhtVejt7c%3D 11803474
S.L. Volchenboum et al. Gene expression profiling of ewing sarcoma tumors reveals the prognostic importance of tumor-stromal interactions: a report from the children’s oncology group J. Pathol. Clin. Res. 1 83 94 1:CAS:528:DC%2BC28XhtlansbjF 26052443 4457396
K. Scotlandi et al. Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome J. Clin. Oncol. 27 2209 2216 1:CAS:528:DC%2BD1MXlvFOgs78%3D 19307502
S. Savola et al. High expression of complement component 5 (C5) at tumor site associates with superior survival in Ewing’s sarcoma family of tumour patients ISRN Oncol. 2011 168712 22084725 3196920
S. Postel-Vinay et al. Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma Nat. Genet 44 323 327 1:CAS:528:DC%2BC38XitFalt7c%3D 22327514
Vanharanta, S. et al. Loss of the multifunctional RNA-binding protein RBM47 as a source of selectable metastatic traits in breast cancer. Elife3, e02734 (2014).
P. Griseri G. Pagès Regulation of the mRNA half-life in breast cancer World J. Clin. Oncol. 5 323 334 25114848 4127604
M. Choder mRNA imprinting: additional level in the regulation of gene expression Cell Logist. 1 37 40 21686103 3109458
A. Boija et al. Transcription factors activate genes through the phase-separation capacity of their activation domains Cell 175 1842 1855.e16 1:CAS:528:DC%2BC1cXit1Wlt7%2FM 30449618
D. Hnisz K. Shrinivas R.A. Young A.K. Chakraborty P.A. Sharp A phase separation model for transcriptional control Cell 169 13 23 1:CAS:528:DC%2BC2sXltVWnsrY%3D 28340338 5432200
Chong, S. et al. Imaging dynamic and selective low-complexity domain interactions that control gene transcription. Science361, eaar2555 (2018).
S.F. Banani et al. Compositional Control of Phase-Separated Cell. Bodies. Cell 166 651 663 1:CAS:528:DC%2BC28XhtFait7jJ 27374333
S. Chong et al. Tuning levels of low-complexity domain interactions to modulate endogenous oncogenic transcription Mol. Cell 82 2084 2097.e5 1:CAS:528:DC%2BB38XhtFejtbvP 35483357
D.M. Mitrea M. Mittasch B.F. Gomes I.A. Klein M.A. Murcko Modulating biomolecular condensates: a novel approach to drug discovery Nat. Rev. Drug Discov. 21 841 862 1:CAS:528:DC%2BB38XitFGjsrfJ 35974095 9380678
M. Biesaga M. Frigolé-Vivas X. Salvatella Intrinsically disordered proteins and biomolecular condensates as drug targets Curr. Opin. Chem. Biol. 62 90 100 1:CAS:528:DC%2BB3MXotVWltbY%3D 33812316 7616887
S. Basu et al. Rational optimization of a transcription factor activation domain inhibitor Nat. Struct. Mol. Biol. 30 1958 1969 1:CAS:528:DC%2BB3sXisFagsrjJ 38049566 10716049
A. Arvand S.M. Welford M.A. Teitell C.T. Denny The COOH-terminal domain of FLI-1 is necessary for full tumorigenesis and transcriptional modulation by EWS/FLI-1 Cancer Res 61 5311 5317 1:CAS:528:DC%2BD3MXltVCjsL0%3D 11431376
J. Wang et al. Multiple functions of the RNA-binding protein HuR in cancer progression, treatment responses and prognosis Int J. Mol. Sci. 14 10015 10041 23665903 3676826
A. Marchetto et al. Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma Nat. Commun. 11 2020NatCo.11.2423M 1:CAS:528:DC%2BB3cXpslyrsrw%3D 32415069 7228971 2423
X.A. Su et al. RAD21 is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress Genes Dev. 35 556 572 1:CAS:528:DC%2BB3MXhtF2itbrI 33766983 8015718
J. Yue et al. The multifaceted mechanisms of Dihydrotanshinone I in the treatment of tumors Biomed. Pharmacother. 175 116635 1:CAS:528:DC%2BB2cXhtVaqtbnO 38653110
I.I. Atanassov I.I. Atanassov J.P. Etchells S.R. Turner A simple, flexible and efficient PCR-fusion/Gateway cloning procedure for gene fusion, site-directed mutagenesis, short sequence insertion and domain deletions and swaps Plant Methods 5 19863796 2775020 14
J. Lykke-Andersen M.D. Shu J.A. Steitz Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon Cell 103 1121 1131 1:CAS:528:DC%2BD3MXit1ajtA%3D%3D 11163187
L. Twyffels et al. A masked PY-NLS in Drosophila TIS11 and its mammalian homolog tristetraprolin PLoS ONE 8 e71686 2013PLoSO..871686T 1:CAS:528:DC%2BC3sXhtlams7fK 23951221 3739726
A. Dobin et al. STAR: ultrafast universal RNA-seq aligner Bioinformatics 29 15 21 1:CAS:528:DC%2BC38XhvV2gsbnF 23104886
S. Anders P.T. Pyl W. Huber HTSeq-a Python framework to work with high-throughput sequencing data Bioinformatics 31 166 169 1:CAS:528:DC%2BC28Xht1Sjt7vL 25260700
M.I. Love W. Huber S. Anders Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 15 25516281 4302049 550
D. Kim J.M. Paggi C. Park C. Bennett S.L. Salzberg Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype Nat. Biotechnol. 37 907 915 1:CAS:528:DC%2BC1MXhsFWqtL7O 31375807 7605509
R.C. McLeay T.L. Bailey Motif Enrichment Analysis: a unified framework and an evaluation on ChIP data BMC Bioinforma. 11 165
B. Mészáros G. Erdos Z. Dosztányi IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding Nucleic Acids Res. 46 W329 W337 29860432 6030935
Z. Obradovic et al. Predicting intrinsic disorder from amino acid sequence Proteins 53 566 572 1:CAS:528:DC%2BD3sXptVygtbk%3D 14579347
Z.R. Yang R. Thomson P. McNeil R.M. Esnouf RONN: the bio-basis function neural network technique applied to the detection of natively disordered regions in proteins Bioinformatics 21 3369 3376 1:CAS:528:DC%2BD2MXovVKru7k%3D 15947016
J. Hanson Y. Yang K. Paliwal Y. Zhou Improving protein disorder prediction by deep bidirectional long short-term memory recurrent neural networks Bioinformatics 33 685 692 28011771
S. Wang J. Ma J. Xu AUCpreD: proteome-level protein disorder prediction by AUC-maximized deep convolutional neural fields Bioinformatics 32 i672 i679 1:CAS:528:DC%2BC28Xhs1aisLrL 27587688 5013916
I. Walsh A.J.M. Martin T. Di Domenico S.C.E. Tosatto ESpritz: accurate and fast prediction of protein disorder Bioinformatics 28 503 509 1:CAS:528:DC%2BC38Xis1entbk%3D 22190692
L.P. Kozlowski J.M. Bujnicki MetaDisorder: a meta-server for the prediction of intrinsic disorder in proteins BMC Bioinforma. 13 2012IAUS.282.111K 111
S. Hirose K. Shimizu S. Kanai Y. Kuroda T. Noguchi POODLE-L: a two-level SVM prediction system for reliably predicting long disordered regions Bioinformatics 23 2046 2053 1:CAS:528:DC%2BD2sXhtVWqtrvE 17545177
J. Jumper et al. Highly accurate protein structure prediction with AlphaFold Nature 596 583 589 2021Natur.596.583J 1:CAS:528:DC%2BB3MXhvVaktrrL 34265844 8371605
M. Varadi et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models Nucleic Acids Res. 50 D439 D444 1:CAS:528:DC%2BB38Xis1Churw%3D 34791371
Pabis, M. et al. HuR biological function involves RRM3-mediated dimerization and RNA binding by all three RRMs. Nucleic Acids Res. 47, 1011−1029 (2019).
S.J. de Vries M. van Dijk A.M.J.J. Bonvin The HADDOCK web server for data-driven biomolecular docking Nat. Protoc. 5 883 897 20431534
H.J.C. Berendsen D. van der Spoel R. van Drunen GROMACS: A message-passing parallel molecular dynamics implementation Comput Phys. Commun. 91 43 56 1995CoPhC.91..43B 1:CAS:528:DyaK2MXps1Wrtr0%3D
M.J. Abraham et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers SoftwareX 1–2 19 25 2015SoftX..1..19A
R.B. Best et al. Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles J. Chem. Theory Comput 8 3257 3273 1:CAS:528:DC%2BC38XhtVKqurfP 23341755 3549273
W. Humphrey A. Dalke K. Schulten VMD: visual molecular dynamics J. Mol. Graph 14 33 38 1:CAS:528:DyaK28Xis12nsrg%3D 8744570
M.C. Baldauf et al. Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets Oncotarget 9 1587 1601 29416716
C.K. Stein et al. Removing batch effects from purified plasma cell gene expression microarrays with modified ComBat BMC Bioinforma. 16 63
V.J. Ebegboni et al. ETS1, a Target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3 Mol. Cancer Res. 22 625 641 1:CAS:528:DC%2BB2cXitFentrnL 38588446 11219265
Buchou, C. et al. Upregulation of the mevalonate pathway through EWSR1-FLI1/EGR2 regulatory axis confers ewing cells exquisite sensitivity to statins. Cancers14, 2327 (2022).
Lindén, M. et al. FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex. EMBO Rep.20, e45766 (2019).
