title: Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics.
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.
authors.affiliation: Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Le
authors.initials: L
authors.lastname: Su
authors.forename: Arthur V
authors.initials: AV
authors.lastname: Sampaio
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jones
authors.forename: Marina
authors.initials: M
authors.lastname: Pacheco
authors.forename: Angela
authors.initials: A
authors.lastname: Goytain
authors.forename: Shujun
authors.initials: S
authors.lastname: Lin
authors.forename: Neal
authors.initials: N
authors.lastname: Poulin
authors.forename: Lin
authors.initials: L
authors.lastname: Yi
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Rossi
authors.forename: Juergen
authors.initials: J
authors.lastname: Kast
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism; D013584:Sarcoma, Synovial / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000970:Antineoplastic Agents; D056970:Co-Repressor Proteins; D056572:Histone Deacetylase Inhibitors; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C116512:SYT-SSX fusion protein; C499043:TLE1 protein, human