Suppression of deacetylase SIRT1 mediates tumor suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma
Menée sur des lignées cellulaires et à l'aide de xénogreffes sur des poissons-zèbres, cette étude suggère l'intérêt d'utiliser des inhibiteurs de SIRT1 pour le traitement des patients atteints d'un sarcome d'Ewing de stade métastatique
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 due to SIRT1 overexpression. In Ewing sarcoma (ES) cells, NOTCH signaling was 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 ES cells, B cell tumors and human keratinocytes where NOTCH dysregulation has been implicated pathogenically. Notably, the SIRT1/2 inhibitor Tenovin-6 killed ES 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 ES metastasis and poor prognosis. Our findings suggest a mechanistic rationale for the use of SIRT1 inhibitors being developed to treat metastatic disease in ES patients.