Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma

Jozef Ban, Dave N T Aryee, Argyro Fourtouna, Wietske Van Der Ent, Max Kauer, Stephan Niedan, Isidro Machado, Carlos Rodriguez-Galindo, Oscar M. Tirado, Raphaela Schwentner, Piero Picci, Adrienne M. Flanagan, Verena Berg, Sandra J. Strauss, Katia Scotlandi, Elizabeth R. Lawlor, Ewa Snaar-Jagalska, Antonio Llombart-Bosch, Heinrich Kovar

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Abstract

The developmental receptor NOTCH plays an important role in various human cancers as a consequence of oncogenic mutations. Here we describe a novel mechanism of NOTCH-induced tumor suppression involving modulation of the deacetylase SIRT1, providing a rationale for the use of SIRT1 inhibitors to treat cancers where this mechanism is inactivated because of SIRT1 overexpression. In Ewing sarcoma cells, NOTCH signaling is abrogated by the driver oncogene EWS-FLI1. Restoration of NOTCH signaling caused growth arrest due to activation of the NOTCH effector HEY1, directly suppressing SIRT1 and thereby activating p53. This mechanism of tumor suppression was validated in Ewing sarcoma cells, B-cell tumors, and human keratinocytes where NOTCH dysregulation has been implicated pathogenically. Notably, the SIRT1/2 inhibitor Tenovin-6 killed Ewing sarcoma cells in vitro and prohibited tumor growth and spread in an established xenograft model in zebrafish. Using immunohistochemistry to analyze primary tissue specimens, we found that high SIRT1 expression was associated with Ewing sarcoma metastasis and poor prognosis. Our findings suggest a mechanistic rationale for the use of SIRT1 inhibitors being developed to treat metastatic disease in patients with Ewing sarcoma.

Original languageEnglish
Pages (from-to)6578-6588
Number of pages11
JournalCancer Research
Volume74
Issue number22
DOIs
Publication statusPublished - Nov 15 2014

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Ban, J., Aryee, D. N. T., Fourtouna, A., Van Der Ent, W., Kauer, M., Niedan, S., Machado, I., Rodriguez-Galindo, C., Tirado, O. M., Schwentner, R., Picci, P., Flanagan, A. M., Berg, V., Strauss, S. J., Scotlandi, K., Lawlor, E. R., Snaar-Jagalska, E., Llombart-Bosch, A., & Kovar, H. (2014). Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma. Cancer Research, 74(22), 6578-6588. https://doi.org/10.1158/0008-5472.CAN-14-1736