TY - JOUR
T1 - Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma
AU - Ban, Jozef
AU - Aryee, Dave N T
AU - Fourtouna, Argyro
AU - Van Der Ent, Wietske
AU - Kauer, Max
AU - Niedan, Stephan
AU - Machado, Isidro
AU - Rodriguez-Galindo, Carlos
AU - Tirado, Oscar M.
AU - Schwentner, Raphaela
AU - Picci, Piero
AU - Flanagan, Adrienne M.
AU - Berg, Verena
AU - Strauss, Sandra J.
AU - Scotlandi, Katia
AU - Lawlor, Elizabeth R.
AU - Snaar-Jagalska, Ewa
AU - Llombart-Bosch, Antonio
AU - Kovar, Heinrich
PY - 2014/11/15
Y1 - 2014/11/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-14-1736
DO - 10.1158/0008-5472.CAN-14-1736
M3 - Article
C2 - 25281719
AN - SCOPUS:84918558904
VL - 74
SP - 6578
EP - 6588
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 22
ER -