Journal
CANCER RESEARCH
Volume 74, Issue 22, Pages 6578-6588Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-1736
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Funding
- European Commission [259348]
- Austrian Science Fund [P22328-B09, I1225-B19]
- Fondo de Investigaciones Sanitarias-ISCIII-FEDER [CES12/021, PI110038]
- National Institute for Health Research, University College London Hospitals Biomedical Research Centre
- UCL Experimental Cancer Centre
- Austrian Science Fund (FWF) [I 1225] Funding Source: researchfish
- Austrian Science Fund (FWF) [I1225, P22328] Funding Source: Austrian Science Fund (FWF)
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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. (C) 2014 AACR.
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