The (Epi)genetics of human synovial sarcoma

Abstract

Human synovial sarcomas are aggressive soft tissue tumors with relatively high rates of recurrences and metastases. They display a variable response to common treatment protocols such as radiation and chemotherapy. For the development of novel diagnostic, prognostic, and therapeutic approaches, detailed information on the molecular mechanisms underlying the development of these tumors is of imperative importance. Fusion of the SS18 and (one of the) SSX genes is a molecular hallmark of human synovial sarcomas. The SS18 and SSX genes encode nuclear proteins that exhibit opposite transcription regulatory activities, likely through epigenetic mechanisms. The SS18 protein functions as a transcriptional coactivator and interacts directly with members of the epigenetic chromatin remodeling and modification machineries. In contrast, the SSX proteins function as transcriptional corepressors and are associated with several Polycomb group proteins. Since the domains involved in these apparently opposite transcription regulatory activities are retained in the SS18-SSX fusion proteins, we hypothesize that these fusion proteins function as "activator-repressors" of transcription. The implications of this model for human synovial sarcoma development and future treatment are discussed.

Histone Deacetylase Inhibitors Reverse SS18-SSX–Mediated Polycomb Silencing of the Tumor Suppressor Early Growth Response 1 in Synovial Sarcoma

“…Microarray hybridization and washing was performed using standard procedures ( full details are available online). 5 Microarrays were scanned on a GenePix 4000 microarray scanner and fluorescence ratios (tumor/reference) were calculated using GenePix software. In this study, expression analysis was limited to the EGR1 gene and to a published list of 55 EGR1 targets (28).…”

“…This translocation results in a fusion of SS18 (also known as SYT) on chromosome 18 to either the SSX1, SSX2, or SSX4 gene on the X chromosome, creating a fusion oncogene believed to be the main molecular basis of this disease (5). Although neither SS18 nor SSX has a recognizable DNA-binding domain, SS18 is able to transactivate and SSX is able to repress transcription when targeted to a reporter gene (6,7).…”

“…The SS18-SSX fusion thus brings together two protein domains, which associate with opposing chromatin remodeling complexes, and most likely leads to development of the disease by disrupting epigenetic regulation of gene expression (5). SS18 is widely expressed in both embryonic and adult tissues (12), whereas SSX proteins belong to the cancer/testis antigens normally expressed only in cells of germ-line and placenta but often reactivated in cancer (13), suggesting that the oncogenic potential of the fusion may come in part from reactivation of SSX functions.…”

The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability

“…In synovial sarcoma, the chromosomal translocation results in the production of a proto-oncogene with dual features of a transactivator and repressor. The resultant fusion protein is presumed to function as an aberrant transcription factor through the misdirected targeting of interacting partners and alteration of epigenetic control (21,22). Interestingly, in comparison with other tumor types, synovial sarcomas display a remarkably low number of mutations in the p53 gene, implying that defects in upstream pathways may be responsible for loss of p53-mediated tumor suppression (23,24).…”

Sarcoma synoviale

“…Az SS és pél-dául a malignus perifériás ideghüvely-daganat (MPNST) azonos kategóriába sorolható, hiszen e két lágyrész-sarcoma számos, a neuralis differenciálódással kapcsolatos génexpressziós mintázatban megegyezik [13]. A legtöbb (>95%) [14] SS-ben kimutatható reverz transzkripciós polimeráz láncreakció (RT-PCR) módszerrel a 18-as és az X-kromoszóma közötti transzlokáció. A SYT (synaptotagmin) és az SSX (synovial sarcoma; X breakpoint) régiók áthelyeződése következtében három fúziós fehér-je képződhet: SYT-SSX1 [15], SYT-SSX2 [16] és SYT-SSX4 [17].…”