PUBLICATION
Suppression of Deacetylase SIRT1 Mediates Tumor-Suppressive NOTCH Response and Offers a Novel Treatment Option in Metastatic Ewing Sarcoma
- Authors
- Ban, J., Aryee, D.N., 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.
- ID
- ZDB-PUB-141005-2
- Date
- 2014
- Source
- Cancer research 74(22): 6578-88 (Journal)
- Registered Authors
- Snaar-Jagalska, Ewa B., van der Ent, Wietske
- Keywords
- none
- MeSH Terms
-
- Animals
- Apoptosis
- Basic Helix-Loop-Helix Transcription Factors/physiology
- Bone Neoplasms/drug therapy*
- Bone Neoplasms/pathology
- Cell Line, Tumor
- Humans
- Neoplasm Metastasis
- Oncogene Proteins, Fusion/physiology
- Proto-Oncogene Protein c-fli-1/physiology
- RNA-Binding Protein EWS/physiology
- Receptors, Notch/physiology*
- Repressor Proteins/physiology
- Sarcoma, Ewing/drug therapy*
- Sarcoma, Ewing/pathology
- Signal Transduction
- Sirtuin 1/analysis
- Sirtuin 1/antagonists & inhibitors
- Sirtuin 1/physiology*
- Tumor Suppressor Protein p53/physiology
- Zebrafish
- PubMed
- 25281719 Full text @ Cancer Res.
Citation
Ban, J., Aryee, D.N., 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):6578-88.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping