SS18–SSX couples ATF2 DNA-binding activity to TLE1-mediated epigenetic repression.

  • Major finding: SS18–SSX couples ATF2 DNA-binding activity to TLE1-mediated epigenetic repression.

  • Clinical relevance: HDAC inhibitors interfere with TLE1 recruitment and rescue ATF2 target gene expression.

  • Impact: These findings provide insight into the function of the SS18–SSX oncoprotein.

Synovial sarcomas are aggressive soft-tissue tumors frequently occurring near joints that are characterized by a SS18–SSX fusion transcript resulting from a reciprocal translocation between chromosomes 18 and X. Because of its association with chromatin remodeling proteins and the sensitivity of synovial sarcoma cells to histone deacetylase (HDAC) inhibitors, the SS18–SSX oncoprotein is thought to drive epigenetically mediated transcriptional deregulation, but its mechanism of action has remained unknown. To gain insight into the role of SS18–SSX, Su and colleagues immunoprecipitated SS18–SSX from synovial sarcoma cells and identified interacting proteins via mass spectrometry. Two master transcriptional regulators, activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1) were identified as SS18–SSX interactors and were both required for synovial sarcoma cell growth and colony formation. ATF2 and TLE1 did not interact in the absence of SS18–SSX, suggesting that the fusion oncoprotein acts as a scaffold to bring these proteins together. ATF2 was required for recruiting SS18–SSX and TLE1 to cAMP-responsive elements, which provides a potential explanation for how SS18–SSX might regulate transcription without being able to directly bind DNA. TLE1 was responsible for incorporating EZH2 and HDAC1 into the SS18–SSX complex, which was associated with increased histone H3 lysine-27 trimethylation and suppression of ATF2 target gene expression. ATF2 target gene expression could be restored by HDAC inhibition, which inhibited TLE1 recruitment to the SS18–SSX complex. Together, these findings suggest that SS18–SSX couples ATF2 and TLE1 activity to suppress ATF2 targets and provide a mechanistic rationale for the use of HDAC inhibitors in synovial sarcoma treatment.

Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A, Lin S, et al. Deconstruction of the SS18–SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell 2012;21:333–47.

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