title: The synovial-sarcoma-associated SS18-SSX2 fusion protein induces epigenetic gene (de)regulation.
abstract: Fusion of the SS18 and either one of the SSX genes is a hallmark of human synovial sarcoma. The SS18 and SSX genes encode nuclear proteins that exhibit opposite transcriptional activities. The SS18 protein functions as a transcriptional coactivator and is associated with the SWI/SNF complex, whereas the SSX proteins function as transcriptional corepressors and are associated with the polycomb complex. The domains involved in these opposite transcriptional activities are retained in the SS18-SSX fusion proteins. Here, we set out to determine the direct transcriptional consequences of conditional SS18-SSX2 fusion protein expression using complementary DNA microarray-based profiling. By doing so, we identified several clusters of SS18-SSX2-responsive genes, including a group of genes involved in cholesterol synthesis, which is a general characteristic of malignancy. In addition, we identified a group of SS18-SSX2-responsive genes known to be specifically deregulated in primary synovial sarcomas, including IGF2 and CD44. Furthermore, we observed an uncoupling of EGR1, JUNB, and WNT signaling in response to SS18-SSX2 expression, suggesting that the SWI/SNF-associated coactivation functions of the SS18 moiety are impaired. Finally, we found that SS18-SSX2 expression affects histone modifications in the CD44 and IGF2 promoters and DNA methylation levels in the IGF2 imprinting control region. Together, we conclude that the SS18-SSX2 fusion protein may act as a so-called transcriptional "activator-repressor," which induces downstream target gene deregulation through epigenetic mechanisms. Our results may have implications for both the development and clinical management of synovial sarcomas.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Diederik R H
authors.initials: DR
authors.lastname: de Bruijn
authors.forename: Susanne V
authors.initials: SV
authors.lastname: Allander
authors.forename: Anke H A
authors.initials: AH
authors.lastname: van Dijk
authors.forename: Marieke P
authors.initials: MP
authors.lastname: Willemse
authors.forename: Jose
authors.initials: J
authors.lastname: Thijssen
authors.forename: Jan J M
authors.initials: JJ
authors.lastname: van Groningen
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
mesh_terms: D002784:Cholesterol / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D013584:Sarcoma, Synovial / Q000235:genetics* / Q000378:metabolism; D013002:Somatomedins / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D006657:Histones; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; C116512:SYT-SSX fusion protein; D013002:Somatomedins; D007335:Insulin-Like Growth Factor II; D002784:Cholesterol