The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes

García-García, Laura; Fernández-Tabanera, Enrique; Cervera, Saint T.; Mera, Raquel M. Melero-Fernández de; Josa, Santiago; González-González, Laura; Rodríguez-Martín, Carlos; Grünewald, Thomas G.P.; Alonso, Javier

doi:10.3390/cancers13225668

Cited by 5 publications

(4 citation statements)

References 51 publications

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“…With the inclusion of EWS/FLI mediated chromatin loops, we identified 193 genes that are dysregulated by a conserved EWS/FLI peak associated with a gained loop in EF-Endo versus EF-KD. These include genes that were previously shown to be EWS/FLI responsive and play important roles in tumor growth and/or metastasis in Ewing sarcoma, such as NKX2-2 ( 8 , 15 ), PPP1R1A ( 70 ), HOXD13 ( 71 ), FEZF1 ( 11 , 72 ), CCND1 ( 15 , 73 ) and CAV1 ( 74 ). We also identified target genes that code for surface proteins, such as SLC24A3 , NTNG1 , LINGO1 and PAPPA , reported as potential candidates for antibody-mediated therapies in Ewing sarcoma ( 75 , 76 ).…”

Section: Resultsmentioning

confidence: 99%

EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma

Showpnil

Selich‐Anderson

Taslim

et al. 2022

Nucleic Acids Research

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Ewing sarcoma is a prototypical fusion transcription factor-associated pediatric cancer that expresses EWS/FLI or a highly related FET/ETS chimera. EWS/FLI dysregulates transcription to induce and maintain sarcomagenesis, but the mechanisms utilized are not fully understood. We therefore sought to define the global effects of EWS/FLI on chromatin conformation and transcription in Ewing sarcoma cells using a well-validated ‘knock-down/rescue’ model of EWS/FLI function in combination with next generation sequencing assays to evaluate how the chromatin landscape changes with loss, and recovery, of EWS/FLI expression. We found that EWS/FLI (and EWS/ERG) genomic localization is largely conserved across multiple patient-derived Ewing sarcoma cell lines. This EWS/FLI binding signature is associated with establishment of topologically-associated domain (TAD) boundaries, compartment activation, enhancer-promoter looping that involve both intra- and inter-TAD interactions, and gene activation. In addition, EWS/FLI co-localizes with the loop-extrusion factor cohesin to promote chromatin loops and TAD boundaries. Importantly, local chromatin features provide the basis for transcriptional heterogeneity in regulation of direct EWS/FLI target genes across different Ewing sarcoma cell lines. These data demonstrate a key role of EWS/FLI in mediating genome-wide changes in chromatin configuration and support the notion that fusion transcription factors serve as master regulators of three-dimensional reprogramming of chromatin.

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Section: Resultsmentioning

confidence: 99%

EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma

Showpnil

Selich‐Anderson

Taslim

et al. 2022

Nucleic Acids Research

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“…Another developmental TF, RUNX3, can directly interact with EWS::FLI1 and coordinately regulate a subset of activated and repressed target genes ( 80 ). For FEZF1, a TF involved in nervous system development, 38% of FEZF1-regulated genes are also EWS::FLI1 target genes ( 81 ). In addition, EWS::FLI1 directly activates E2F family TFs, specifically E2F3, which positively regulate EWS::FLI1-activated genes and promote proliferation ( 82 , 83 ).…”

Section: Cell Autonomous Regulators Of Ews::fli1 Transcript Expressionmentioning

confidence: 99%

“…A recent study found that 14% of all TFs are regulated by EWS::FLI1, resulting in cascading downstream effects on the cell transcriptome ( 81 ). In addition to the TFs mentioned above, EWS::FLI1 can modulate the expression of the Hedgehog signaling mediator GLI1 ( 83 , 93 ), pluripotency TF SOX2 ( 38 , 51 ), the neural crest and myogenic developmental TF PAX7 ( 94 , 95 ), neurodevelopmental TF EGR2 ( 96 , 97 ), the blood and bone developmental TF SOX6 ( 45 ), FOXO1 ( 98 ), and AP1 ( 99 ).…”

Section: Cell Autonomous Regulators Of Ews::fli1 Transcript Expressionmentioning

confidence: 99%

The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review

2022

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Accumulating evidence shows that despite clonal origins tumors eventually become complex communities comprised of phenotypically distinct cell subpopulations. This heterogeneity arises from both tumor cell intrinsic programs and signals from spatially and temporally dynamic microenvironments. While pediatric cancers usually lack the mutational burden of adult cancers, they still exhibit high levels of cellular heterogeneity that are largely mediated by epigenetic mechanisms. Ewing sarcomas are aggressive bone and soft tissue malignancies with peak incidence in adolescence and the prognosis for patients with relapsed and metastatic disease is dismal. Ewing sarcomas are driven by a single pathognomonic fusion between a FET protein and an ETS family transcription factor, the most common of which is EWS::FLI1. Despite sharing a single driver mutation, Ewing sarcoma cells demonstrate a high degree of transcriptional heterogeneity both between and within tumors. Recent studies have identified differential fusion protein activity as a key source of this heterogeneity which leads to profoundly different cellular phenotypes. Paradoxically, increased invasive and metastatic potential is associated with lower EWS::FLI1 activity. Here, we review what is currently understood about EWS::FLI1 activity, the cell autonomous and tumor microenvironmental factors that regulate it, and the downstream consequences of these activity states on tumor progression. We specifically highlight how transcription factor regulation, signaling pathway modulation, and the extracellular matrix intersect to create a complex network of tumor cell phenotypes. We propose that elucidation of the mechanisms by which these essential elements interact will enable the development of novel therapeutic approaches that are designed to target this complexity and ultimately improve patient outcomes.

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“…Thus, deciphering the contribution of specific genes to Ewing sarcoma phenotypes is relevant to understanding Ewing sarcoma biology and identifying pathways involved in proliferation and migration/invasiveness. Our research group has predominantly focused on looking up genes regulated positively or negatively by EWSR1::FLI1 in Ewing sarcoma cells (e.g., NR0B1/DAX1, CCK, LOX, SPRY1, DKK2, or FEZF1) [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

CD44 Modulates Cell Migration and Invasion in Ewing Sarcoma Cells

Fernández-Tabanera

García-García

Rodríguez-Martín

et al. 2023

IJMS

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The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1low cells present a migratory and invasive phenotype, while EWSR1::FLI1high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells.

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The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes

Cited by 5 publications

References 51 publications

EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma

EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma

The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review

CD44 Modulates Cell Migration and Invasion in Ewing Sarcoma Cells

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