title: Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma.
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.
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Jozef
authors.initials: J
authors.lastname: Ban
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria. Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Dave N T
authors.initials: DN
authors.lastname: Aryee
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Argyro
authors.initials: A
authors.lastname: Fourtouna
authors.affiliation: Institute of Biology and Department of Pathology, Leiden University, Leiden, The Netherlands.
authors.forename: Wietske
authors.initials: W
authors.lastname: van der Ent
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Max
authors.initials: M
authors.lastname: Kauer
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Niedan
authors.affiliation: Department of Pathology, University Medical School, València, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Machado
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.affiliation: Laboratori d'Oncología Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Tirado
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Schwentner
authors.affiliation: Laboratory of Experimental Oncology, Rizzoli Institute, Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Berg
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Strauss
authors.affiliation: Laboratory of Experimental Oncology, Rizzoli Institute, Bologna, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
authors.affiliation: Translational Oncology Program, Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Lawlor
authors.affiliation: Institute of Biology and Department of Pathology, Leiden University, Leiden, The Netherlands.
authors.forename: Ewa
authors.initials: E
authors.lastname: Snaar-Jagalska
authors.affiliation: Department of Pathology, University Medical School, València, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Llombart-Bosch
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria. Department of Pediatrics, Medical University of Vienna, Vienna, Austria. heinrich.kovar@ccri.at.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kovar
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology; D034802:RNA-Binding Protein EWS / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D015027:Zebrafish
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D051880:Receptors, Notch; D012097:Repressor Proteins; D056564:Sirtuin 1; D016159:Tumor Suppressor Protein p53; C106031:EWS-FLI fusion protein; C405694:Hairy, HRT1 protein; C495901:TP53 protein, human; C447939:SIRT1 protein, human