The molecular basis of SS18-SSX action in synovial sarcoma

Synovial sarcoma is a highly invasive soft tissue malignancy of young people, for which current treatment provides limited benefit. A chromosomal translocation t(X;18) is characteristic of this disease, and the resulting fusion SS18-SSX acts as an oncoprotein that promotes synovial sarcoma oncogenesis through unclear mechanisms. The work presented in this thesis aims to understand the molecular basis of SS18-SSX oncogenic action. Using patient-derived synovial sarcoma cells, we characterized a multicomponent SS18-SSX complex and discovered a scaffolding role for SS18-SSX in connecting two previously unlinked molecules, activating transcription factor 2 (ATF-2) and transducin-like enhancer of split 1 (TLE1). The latter recruits Polycomb-group (PcG)/histone deacetylase (HDAC) repressors to SS18-SSX transcriptional complex, to silence ATF-2 target genes. In accordance with this model, HDAC inhibitors effectively reverse PcG/HDAC-mediated epigenetic repression, rescue the expression of SS18-SSX target genes, and suppress synovial sarcoma tumor cell survival. Beyond this finding, we further showed that treatment with HDAC inhibitors prevents TLE1 recruitment and triggers SS18-SSX oncoprotein degradation, thereby disrupting this aberrant transcriptional complex. Collectively, these findings advance our understanding of the molecular mechanisms underlying SS18-SSX action in synovial sarcoma pathogenesis. This thesis also provides further support for the clinical evaluation of HDAC inhibitors alone or in combination with other agents to treat synovial sarcoma.Medicine, Faculty ofGraduat