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 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