EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma
Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver onc...
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| Veröffentlicht in: | Oncogene 2017-10, Vol.36 (43), p.5995-6005 |
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| description | Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, affecting the expression of a large number of EWS-FLI1-anticorrelated genes including structural and regulatory cytoskeletal genes. Consistent with this finding, chromatin immunoprecipitation sequencing (ChIP-seq) revealed strong overlaps in myocardin-related transcription factor B (MRTFB) and EWS-FLI1 chromatin occupation, especially for EWS-FLI1-anticorrelated genes. Binding of the transcriptional co-activator Yes-associated protein (YAP)-1, enrichment of TEAD-binding motifs in these shared genomic binding regions and overlapping transcriptional footprints of MRTFB and TEAD factors led us to propose synergy between MRTFB and the YAP/TEAD complex in the regulation of EWS-FLI1-anticorrelated genes. We propose that EWS-FLI1 suppresses the Rho-actin pathway by perturbation of a MRTFB/YAP-1/TEAD transcriptional module, which directly affects the actin-autoregulatory feedback loop. As spontaneous fluctuations in EWS-FLI1 levels of Ewing sarcoma cells
in vitro
and
in vivo
, associated with a switch between a proliferative, non-migratory EWS-FLI1-high and a non-proliferative highly migratory EWS-FLI1-low state, were recently described, our data provide a mechanistic basis for the underlying EWS-FLI1-dependent reversible cytoskeletal reprogramming of Ewing sarcoma cells. |
| doi_str_mv | 10.1038/onc.2017.202 |
| format | Article |
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in vitro
and
in vivo
, associated with a switch between a proliferative, non-migratory EWS-FLI1-high and a non-proliferative highly migratory EWS-FLI1-low state, were recently described, our data provide a mechanistic basis for the underlying EWS-FLI1-dependent reversible cytoskeletal reprogramming of Ewing sarcoma cells.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2017.202</identifier><identifier>PMID: 28671673</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>14/19 ; 38/61 ; 38/91 ; 631/67/2332 ; 631/67/395 ; Actin ; Actins - genetics ; Apoptosis ; Bone cancer ; Care and treatment ; Cell Biology ; Cell Line, Tumor ; Cell Proliferation - genetics ; Cellular Reprogramming - genetics ; Cellular signal transduction ; Chromatin ; Chromatin - genetics ; Cytoskeleton ; Cytoskeleton - genetics ; Development and progression ; Ewing's sarcoma ; Ewings sarcoma ; Feedback ; Gene Expression Regulation, Neoplastic ; Gene regulation ; Genes ; Genetic aspects ; Health aspects ; Human Genetics ; Humans ; Immunoprecipitation ; Internal Medicine ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Oncogene Proteins, Fusion - genetics ; Oncogenes ; Oncology ; Original ; original-article ; Proto-Oncogene Protein c-fli-1 - genetics ; RNA-Binding Protein EWS - genetics ; Sarcoma, Ewing - genetics ; Sarcoma, Ewing - pathology ; Signal Transduction - genetics ; Yes-associated protein</subject><ispartof>Oncogene, 2017-10, Vol.36 (43), p.5995-6005</ispartof><rights>The Author(s) 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 26, 2017</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c517t-5d067ca1a4c851d43a2e621ca92dfde35b2bf472ee35421691d313c10a89a9c83</citedby><cites>FETCH-LOGICAL-c517t-5d067ca1a4c851d43a2e621ca92dfde35b2bf472ee35421691d313c10a89a9c83</cites><orcidid>0000-0001-6839-0322 ; 0000-0002-6287-8391</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2017.202$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2017.202$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28671673$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Katschnig, A M</creatorcontrib><creatorcontrib>Kauer, M O</creatorcontrib><creatorcontrib>Schwentner, R</creatorcontrib><creatorcontrib>Tomazou, E M</creatorcontrib><creatorcontrib>Mutz, C N</creatorcontrib><creatorcontrib>Linder, M</creatorcontrib><creatorcontrib>Sibilia, M</creatorcontrib><creatorcontrib>Alonso, J</creatorcontrib><creatorcontrib>Aryee, D N T</creatorcontrib><creatorcontrib>Kovar, H</creatorcontrib><title>EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, affecting the expression of a large number of EWS-FLI1-anticorrelated genes including structural and regulatory cytoskeletal genes. Consistent with this finding, chromatin immunoprecipitation sequencing (ChIP-seq) revealed strong overlaps in myocardin-related transcription factor B (MRTFB) and EWS-FLI1 chromatin occupation, especially for EWS-FLI1-anticorrelated genes. Binding of the transcriptional co-activator Yes-associated protein (YAP)-1, enrichment of TEAD-binding motifs in these shared genomic binding regions and overlapping transcriptional footprints of MRTFB and TEAD factors led us to propose synergy between MRTFB and the YAP/TEAD complex in the regulation of EWS-FLI1-anticorrelated genes. We propose that EWS-FLI1 suppresses the Rho-actin pathway by perturbation of a MRTFB/YAP-1/TEAD transcriptional module, which directly affects the actin-autoregulatory feedback loop. As spontaneous fluctuations in EWS-FLI1 levels of Ewing sarcoma cells
in vitro
and
in vivo
, associated with a switch between a proliferative, non-migratory EWS-FLI1-high and a non-proliferative highly migratory EWS-FLI1-low state, were recently described, our data provide a mechanistic basis for the underlying EWS-FLI1-dependent reversible cytoskeletal reprogramming of Ewing sarcoma cells.</description><subject>14/19</subject><subject>38/61</subject><subject>38/91</subject><subject>631/67/2332</subject><subject>631/67/395</subject><subject>Actin</subject><subject>Actins - genetics</subject><subject>Apoptosis</subject><subject>Bone cancer</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - genetics</subject><subject>Cellular Reprogramming - genetics</subject><subject>Cellular signal transduction</subject><subject>Chromatin</subject><subject>Chromatin - genetics</subject><subject>Cytoskeleton</subject><subject>Cytoskeleton - genetics</subject><subject>Development and progression</subject><subject>Ewing's sarcoma</subject><subject>Ewings sarcoma</subject><subject>Feedback</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Internal Medicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Oncogenes</subject><subject>Oncology</subject><subject>Original</subject><subject>original-article</subject><subject>Proto-Oncogene Protein c-fli-1 - genetics</subject><subject>RNA-Binding Protein EWS - genetics</subject><subject>Sarcoma, Ewing - genetics</subject><subject>Sarcoma, Ewing - pathology</subject><subject>Signal Transduction - genetics</subject><subject>Yes-associated protein</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkt9v0zAQxyMEYmXwxjOKxAsPpPU5cX68IHWjhUlFIChCPFmOc8m8JXaxHVD563HUMjY0WTqffJ_7Wnf6RtFzIHMgabkwWs4pgSIE-iCaQVbkCWNV9jCakYqRpKIpPYmeOHdFCCkqQh9HJ7TMC8iLdBb9Xn37kqw3FxDv0PrR1i7-8Hm7Plt8X35KYLFdLd_GXtgOfdyhxthiN_bCK6NjpS9VrbzSXSz33rhr7NGLPhajN0fM2H3cIja1kNeBj1e_JtoJK80gnkaPWtE7fHa8T6Ov69X2_H2y-fju4ny5SSSDwiesIXkhBYhMlgyaLBUUcwpSVLRpG0xZTes2KyiGNKOQV9CkkEogoqxEJcv0NHpz0N2N9YCNRO2t6PnOqkHYPTdC8bsVrS55Z35ylud5SkkQeHUUsObHiM7zQTmJfS80mtFxqICFjZOCBvTlf-iVGa0O4wWKsSxsPcv_UZ3okSvdmvCvnET5kgFkGVA6ac3vocJpcFDSaGxVeL_T8PrQIK1xzmJ7MyMQPnmFB6_wySshTPiL23u5gf-aIwDJAXChpDu0t4a5T_APO_3HyQ</recordid><startdate>20171026</startdate><enddate>20171026</enddate><creator>Katschnig, A M</creator><creator>Kauer, M O</creator><creator>Schwentner, R</creator><creator>Tomazou, E M</creator><creator>Mutz, C N</creator><creator>Linder, M</creator><creator>Sibilia, M</creator><creator>Alonso, J</creator><creator>Aryee, D N T</creator><creator>Kovar, H</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6839-0322</orcidid><orcidid>https://orcid.org/0000-0002-6287-8391</orcidid></search><sort><creationdate>20171026</creationdate><title>EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma</title><author>Katschnig, A M ; Kauer, M O ; Schwentner, R ; Tomazou, E M ; Mutz, C N ; Linder, M ; Sibilia, M ; Alonso, J ; Aryee, D N T ; Kovar, H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c517t-5d067ca1a4c851d43a2e621ca92dfde35b2bf472ee35421691d313c10a89a9c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>14/19</topic><topic>38/61</topic><topic>38/91</topic><topic>631/67/2332</topic><topic>631/67/395</topic><topic>Actin</topic><topic>Actins - genetics</topic><topic>Apoptosis</topic><topic>Bone cancer</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - genetics</topic><topic>Cellular Reprogramming - genetics</topic><topic>Cellular signal transduction</topic><topic>Chromatin</topic><topic>Chromatin - genetics</topic><topic>Cytoskeleton</topic><topic>Cytoskeleton - genetics</topic><topic>Development and progression</topic><topic>Ewing's sarcoma</topic><topic>Ewings sarcoma</topic><topic>Feedback</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene regulation</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Internal Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Oncogene Proteins, Fusion - genetics</topic><topic>Oncogenes</topic><topic>Oncology</topic><topic>Original</topic><topic>original-article</topic><topic>Proto-Oncogene Protein c-fli-1 - genetics</topic><topic>RNA-Binding Protein EWS - genetics</topic><topic>Sarcoma, Ewing - genetics</topic><topic>Sarcoma, Ewing - pathology</topic><topic>Signal Transduction - genetics</topic><topic>Yes-associated protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Katschnig, A M</creatorcontrib><creatorcontrib>Kauer, M O</creatorcontrib><creatorcontrib>Schwentner, R</creatorcontrib><creatorcontrib>Tomazou, E M</creatorcontrib><creatorcontrib>Mutz, C N</creatorcontrib><creatorcontrib>Linder, M</creatorcontrib><creatorcontrib>Sibilia, M</creatorcontrib><creatorcontrib>Alonso, J</creatorcontrib><creatorcontrib>Aryee, D N T</creatorcontrib><creatorcontrib>Kovar, H</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Katschnig, A M</au><au>Kauer, M O</au><au>Schwentner, R</au><au>Tomazou, E M</au><au>Mutz, C N</au><au>Linder, M</au><au>Sibilia, M</au><au>Alonso, J</au><au>Aryee, D N T</au><au>Kovar, H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2017-10-26</date><risdate>2017</risdate><volume>36</volume><issue>43</issue><spage>5995</spage><epage>6005</epage><pages>5995-6005</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, affecting the expression of a large number of EWS-FLI1-anticorrelated genes including structural and regulatory cytoskeletal genes. Consistent with this finding, chromatin immunoprecipitation sequencing (ChIP-seq) revealed strong overlaps in myocardin-related transcription factor B (MRTFB) and EWS-FLI1 chromatin occupation, especially for EWS-FLI1-anticorrelated genes. Binding of the transcriptional co-activator Yes-associated protein (YAP)-1, enrichment of TEAD-binding motifs in these shared genomic binding regions and overlapping transcriptional footprints of MRTFB and TEAD factors led us to propose synergy between MRTFB and the YAP/TEAD complex in the regulation of EWS-FLI1-anticorrelated genes. We propose that EWS-FLI1 suppresses the Rho-actin pathway by perturbation of a MRTFB/YAP-1/TEAD transcriptional module, which directly affects the actin-autoregulatory feedback loop. As spontaneous fluctuations in EWS-FLI1 levels of Ewing sarcoma cells
in vitro
and
in vivo
, associated with a switch between a proliferative, non-migratory EWS-FLI1-high and a non-proliferative highly migratory EWS-FLI1-low state, were recently described, our data provide a mechanistic basis for the underlying EWS-FLI1-dependent reversible cytoskeletal reprogramming of Ewing sarcoma cells.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28671673</pmid><doi>10.1038/onc.2017.202</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6839-0322</orcidid><orcidid>https://orcid.org/0000-0002-6287-8391</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Oncogene, 2017-10, Vol.36 (43), p.5995-6005 |
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| language | eng |
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| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 14/19 38/61 38/91 631/67/2332 631/67/395 Actin Actins - genetics Apoptosis Bone cancer Care and treatment Cell Biology Cell Line, Tumor Cell Proliferation - genetics Cellular Reprogramming - genetics Cellular signal transduction Chromatin Chromatin - genetics Cytoskeleton Cytoskeleton - genetics Development and progression Ewing's sarcoma Ewings sarcoma Feedback Gene Expression Regulation, Neoplastic Gene regulation Genes Genetic aspects Health aspects Human Genetics Humans Immunoprecipitation Internal Medicine Medicine Medicine & Public Health Metastases Metastasis Oncogene Proteins, Fusion - genetics Oncogenes Oncology Original original-article Proto-Oncogene Protein c-fli-1 - genetics RNA-Binding Protein EWS - genetics Sarcoma, Ewing - genetics Sarcoma, Ewing - pathology Signal Transduction - genetics Yes-associated protein |
| title | EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T04%3A36%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=EWS-FLI1%20perturbs%20MRTFB/YAP-1/TEAD%20target%20gene%20regulation%20inhibiting%20cytoskeletal%20autoregulatory%20feedback%20in%20Ewing%20sarcoma&rft.jtitle=Oncogene&rft.au=Katschnig,%20A%20M&rft.date=2017-10-26&rft.volume=36&rft.issue=43&rft.spage=5995&rft.epage=6005&rft.pages=5995-6005&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/onc.2017.202&rft_dat=%3Cgale_pubme%3EA511441222%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1955471646&rft_id=info:pmid/28671673&rft_galeid=A511441222&rfr_iscdi=true |