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The molecular basis of SS18-SSX action in synovial sarcoma

University of British Columbia

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.

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2015-08-31

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/50062

Anatomy, Cell Biology and Physiology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/