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SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas

Oncogene volume 32, pages 2365–2371 (2013)Cite this article

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Abstract

Synovial sarcoma is a deadly malignancy with limited sensitivity to traditional cytotoxic chemotherapy. SS18-SSX fusion oncogene expression characterizes human synovial sarcomas and drives oncogenesis in a mouse model. Elevated expression of BCL2 is considered a consistent feature of the synovial sarcoma expression profile. Our objective was to evaluate the expression of apoptotic pathway members in synovial sarcomas and interrogate the impact of modulating SS18-SSX expression on this pathway. We show in human and murine synovial sarcoma cells that SS18-SSX increases BCL2 expression, but represses other anti-apoptotic genes, including MCL1 and BCL2A1. This repression is achieved by directly suppressing expression via binding through activating transcription factor 2 (ATF2) to the cyclic adenosine monophosphate (AMP) response element (CRE) in the promoters of these genes and recruiting TLE1/Groucho. The suppression of these two anti-apoptotic pathways silences the typical routes by which other tumors evade BH3-domain peptidomimetic pharmacotherapy. We show that mouse and human synovial sarcoma cells are sensitive in vitro to ABT-263, a BH3-peptidomimetic, much more than the other tested cancer cell lines. ABT-263 also enhances the sensitivity of these cells to doxorubicin, a traditional cytotoxic chemotherapy used for synovial sarcoma. We also demonstrate the capacity of ABT-263 to stunt synovial sarcomagenesis in vivo in a genetic mouse model. These data recommend pursuit of BH3-peptidomimetic pharmacotherapy in human synovial sarcomas.

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Acknowledgements

We gratefully acknowledge the support of the Paul Nabil Bustany Fund for Synovial Sarcoma Research, the Huntsman Cancer Foundation, and career development support from National Cancer Institute (NIH) K08CA138764. This work was also supported by grants from the Canadian Cancer Society Research Institute (Grant no.018355) and the Terry Fox Foundation and CIHR Institute of Cancer (TFF 105265). We thank Matt Hockin, PhD, at the University of Utah for producing the TATCre protein.

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Authors and Affiliations

  1. Department of Orthopaedics, University of Utah, Salt Lake City, UT, USA

    K B Jones, H Jin & R L Randall

  2. Center for Children’s Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    K B Jones, H Jin, C Lenz, R L Randall, S Sharma & M R Capecchi

  3. Department of Human Genetics, Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT, USA

    K B Jones, H Jin, C Lenz & M R Capecchi

  4. Department of Pathology and Laboratory Medicine and The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada

    L Su, T M Underhill & T O Nielsen

  5. The Division of Hematology/Oncology, Department of Medicine, University of Utah, Salt Lake City, UT, USA

    S Sharma

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  1. K B Jones
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  2. L Su
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  3. H Jin
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Correspondence to M R Capecchi.

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Jones, K., Su, L., Jin, H. et al. SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas. Oncogene 32, 2365–2371 (2013). https://doi.org/10.1038/onc.2012.247

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