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EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor

Oncogene volume 29, pages 4352–4361 (2010)Cite this article

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Abstract

Synovial sarcoma is a high-grade soft tissue malignancy, for which current cytotoxic chemotherapies provide limited benefit. Although histone deacetylase (HDAC) inhibitors are known to suppress synovial sarcoma in vitro and in vivo, the exact mechanism is not clear. In this study, we report a central role of the transcription factor, early growth response-1 (EGR1), in the regulation of HDAC inhibitor-induced apoptotic cell death in synovial sarcoma. The SS18-SSX oncoprotein, characteristic of synovial sarcoma, maintains EGR1 expression at low levels, whereas it is significantly increased after HDAC inhibitor treatment. On the contrary, EGR1 knockdown leads to a decrease in HDAC inhibitor-induced apoptosis. Moreover, we find that under these conditions phosphatase and tensin homolog deleted in chromosome 10 (PTEN) is upregulated and this occurs through direct binding of EGR1 to an element upstream of the PTEN promoter. Using a combination of gain- and loss-of-function approaches, we show that EGR1 modulation of PTEN contributes to HDAC inhibitor-induced apoptosis in synovial sarcoma. Finally, restoration of EGR1 or PTEN expression is sufficient to induce synovial sarcoma cell death. Taken together, our findings indicate that SS18-SSX-mediated attenuation of an EGR1–PTEN network regulates synovial sarcoma cell survival, and that HDAC inhibitor-mediated apoptosis operates at least in part through reactivation of this pathway.

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Acknowledgements

We thank Dr Diederik RH de Bruijn (Radbound University Nijmegen Medical Centre, Nijmegen, the Netherlands) for the gift of rabbit polyclonal antibody against SS18–SSX. This work was supported by a grant from the Canadian Cancer Society Research Institute (Grant #018355). Dr TO Nielsen is a scholar of the Michael Smith Foundation for Health Research, and Dr TM Underhill is an Arthritis Society Investigator.

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Authors and Affiliations

  1. Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada

    L Su, A V Sampaio & T M Underhill

  2. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    H Cheng & T O Nielsen

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  1. L Su
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Correspondence to T O Nielsen or T M Underhill.

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Su, L., Cheng, H., Sampaio, A. et al. EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor. Oncogene 29, 4352–4361 (2010). https://doi.org/10.1038/onc.2010.204

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Keywords

  • HDAC inhibitors
  • synovial sarcoma
  • EGR1
  • PTEN
  • apoptosis

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