Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics
Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of actio...
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| Veröffentlicht in: | Cancer cell 2012-03, Vol.21 (3), p.333-347 |
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| creator | Su, Le Sampaio, Arthur V. Jones, Kevin B. Pacheco, Marina Goytain, Angela Lin, Shujun Poulin, Neal Yi, Lin Rossi, Fabio M. Kast, Juergen Capecchi, Mario R. Underhill, T. Michael Nielsen, Torsten O. |
| description | Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma.
► SS18-SSX interacts with ATF2 and TLE1 in human synovial sarcoma cells ► ATF2 recruits the SS18-SSX complex to specific gene promoters ► TLE1 is responsible for SS18-SSX-mediated repression of ATF2 targets ► HDAC inhibitors disrupt the SS18-SSX complex |
| doi_str_mv | 10.1016/j.ccr.2012.01.010 |
| format | Article |
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► SS18-SSX interacts with ATF2 and TLE1 in human synovial sarcoma cells ► ATF2 recruits the SS18-SSX complex to specific gene promoters ► TLE1 is responsible for SS18-SSX-mediated repression of ATF2 targets ► HDAC inhibitors disrupt the SS18-SSX complex</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2012.01.010</identifier><identifier>PMID: 22439931</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Activating Transcription Factor 2 - metabolism ; Animals ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; HEK293 Cells ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Mice ; Oncogene Proteins, Fusion - genetics ; Oncogene Proteins, Fusion - metabolism ; Oncogene Proteins, Fusion - physiology ; Repressor Proteins - metabolism ; RNA, Small Interfering ; Sarcoma, Synovial - genetics ; Sarcoma, Synovial - metabolism ; Translocation, Genetic</subject><ispartof>Cancer cell, 2012-03, Vol.21 (3), p.333-347</ispartof><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><rights>2012 Elsevier Inc. All rights reserved. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c450t-54fd0c4cd194471acac5d12cd804ee34744addb18950e67484c1c8ef4c2c64f73</citedby><cites>FETCH-LOGICAL-c450t-54fd0c4cd194471acac5d12cd804ee34744addb18950e67484c1c8ef4c2c64f73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ccr.2012.01.010$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22439931$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Su, Le</creatorcontrib><creatorcontrib>Sampaio, Arthur V.</creatorcontrib><creatorcontrib>Jones, Kevin B.</creatorcontrib><creatorcontrib>Pacheco, Marina</creatorcontrib><creatorcontrib>Goytain, Angela</creatorcontrib><creatorcontrib>Lin, Shujun</creatorcontrib><creatorcontrib>Poulin, Neal</creatorcontrib><creatorcontrib>Yi, Lin</creatorcontrib><creatorcontrib>Rossi, Fabio M.</creatorcontrib><creatorcontrib>Kast, Juergen</creatorcontrib><creatorcontrib>Capecchi, Mario R.</creatorcontrib><creatorcontrib>Underhill, T. Michael</creatorcontrib><creatorcontrib>Nielsen, Torsten O.</creatorcontrib><title>Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma.
► SS18-SSX interacts with ATF2 and TLE1 in human synovial sarcoma cells ► ATF2 recruits the SS18-SSX complex to specific gene promoters ► TLE1 is responsible for SS18-SSX-mediated repression of ATF2 targets ► HDAC inhibitors disrupt the SS18-SSX complex</description><subject>Activating Transcription Factor 2 - metabolism</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Knockdown Techniques</subject><subject>HEK293 Cells</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Mice</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Oncogene Proteins, Fusion - metabolism</subject><subject>Oncogene Proteins, Fusion - physiology</subject><subject>Repressor Proteins - metabolism</subject><subject>RNA, Small Interfering</subject><subject>Sarcoma, Synovial - genetics</subject><subject>Sarcoma, Synovial - metabolism</subject><subject>Translocation, Genetic</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kNtqHDEMhk1paU59gN4Uv8BsrRnPjKeFQtkcGgjkYlPInXFkza6XXXuwvSF5-3rZNjQ3AYGEpP8T-hn7DGIGArqv6xlinNUC6pmAEuIdOwbVq6rpVPe-1G3TVh0IdcROUlqLooF--MiO6lo2w9DAMVufEwafctxhdsHzMPK8Ir5YgKoWi3t-uUv79q3HMMWQyXk-D9tpQ0_f-LVPbrnKiTufAz93iUwiflE4m7B85sZbfreiaCbaZYfpjH0YzSbRp7_5lP2-vLib_6pubq-u5z9vKpStyFUrRytQooVByh4MGmwt1GiVkESN7KU01j6AGlpBXS-VREBFo8QaOzn2zSn7ceBOu4ctWSSfo9noKbqtic86GKdfT7xb6WV41E3fyKGVBQAHAMaQUqTxRQtC743Xa12M13vjtYASomi-_H_0RfHP6bLw_bBA5fVHR1EndOSRrIuEWdvg3sD_AWzFlj0</recordid><startdate>20120320</startdate><enddate>20120320</enddate><creator>Su, Le</creator><creator>Sampaio, Arthur V.</creator><creator>Jones, Kevin B.</creator><creator>Pacheco, Marina</creator><creator>Goytain, Angela</creator><creator>Lin, Shujun</creator><creator>Poulin, Neal</creator><creator>Yi, Lin</creator><creator>Rossi, Fabio M.</creator><creator>Kast, Juergen</creator><creator>Capecchi, Mario R.</creator><creator>Underhill, T. Michael</creator><creator>Nielsen, Torsten O.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>5PM</scope></search><sort><creationdate>20120320</creationdate><title>Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics</title><author>Su, Le ; Sampaio, Arthur V. ; Jones, Kevin B. ; Pacheco, Marina ; Goytain, Angela ; Lin, Shujun ; Poulin, Neal ; Yi, Lin ; Rossi, Fabio M. ; Kast, Juergen ; Capecchi, Mario R. ; Underhill, T. Michael ; Nielsen, Torsten O.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-54fd0c4cd194471acac5d12cd804ee34744addb18950e67484c1c8ef4c2c64f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Activating Transcription Factor 2 - metabolism</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Knockdown Techniques</topic><topic>HEK293 Cells</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Mice</topic><topic>Oncogene Proteins, Fusion - genetics</topic><topic>Oncogene Proteins, Fusion - metabolism</topic><topic>Oncogene Proteins, Fusion - physiology</topic><topic>Repressor Proteins - metabolism</topic><topic>RNA, Small Interfering</topic><topic>Sarcoma, Synovial - genetics</topic><topic>Sarcoma, Synovial - metabolism</topic><topic>Translocation, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Su, Le</creatorcontrib><creatorcontrib>Sampaio, Arthur V.</creatorcontrib><creatorcontrib>Jones, Kevin B.</creatorcontrib><creatorcontrib>Pacheco, Marina</creatorcontrib><creatorcontrib>Goytain, Angela</creatorcontrib><creatorcontrib>Lin, Shujun</creatorcontrib><creatorcontrib>Poulin, Neal</creatorcontrib><creatorcontrib>Yi, Lin</creatorcontrib><creatorcontrib>Rossi, Fabio M.</creatorcontrib><creatorcontrib>Kast, Juergen</creatorcontrib><creatorcontrib>Capecchi, Mario R.</creatorcontrib><creatorcontrib>Underhill, T. Michael</creatorcontrib><creatorcontrib>Nielsen, Torsten O.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Su, Le</au><au>Sampaio, Arthur V.</au><au>Jones, Kevin B.</au><au>Pacheco, Marina</au><au>Goytain, Angela</au><au>Lin, Shujun</au><au>Poulin, Neal</au><au>Yi, Lin</au><au>Rossi, Fabio M.</au><au>Kast, Juergen</au><au>Capecchi, Mario R.</au><au>Underhill, T. Michael</au><au>Nielsen, Torsten O.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2012-03-20</date><risdate>2012</risdate><volume>21</volume><issue>3</issue><spage>333</spage><epage>347</epage><pages>333-347</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma.
► SS18-SSX interacts with ATF2 and TLE1 in human synovial sarcoma cells ► ATF2 recruits the SS18-SSX complex to specific gene promoters ► TLE1 is responsible for SS18-SSX-mediated repression of ATF2 targets ► HDAC inhibitors disrupt the SS18-SSX complex</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22439931</pmid><doi>10.1016/j.ccr.2012.01.010</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete; Cell Press Free Archives; EZB-FREE-00999 freely available EZB journals |
| subjects | Activating Transcription Factor 2 - metabolism Animals Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Line, Tumor Cell Proliferation - drug effects Gene Expression Regulation, Neoplastic Gene Knockdown Techniques HEK293 Cells Histone Deacetylase Inhibitors - pharmacology Humans Mice Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Oncogene Proteins, Fusion - physiology Repressor Proteins - metabolism RNA, Small Interfering Sarcoma, Synovial - genetics Sarcoma, Synovial - metabolism Translocation, Genetic |
| title | Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics |
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