Suppression of Deacetylase SIRT1 Mediates Tumor-Suppressive NOTCH Response and Offers a Novel Treatment Option in Metastatic Ewing Sarcoma

被引：56

作者：

Ban, Jozef ^{[1
]}

Aryee, Dave N. T. ^{[1
,2
]}

Fourtouna, Argyro ^{[1
]}

van der Ent, Wietske ^{[3
,4
]}

Kauer, Max ^{[1
]}

Niedan, Stephan ^{[1
]}

Machado, Isidro ^{[5
]}

Rodriguez-Galindo, Carlos ^{[6
]}

Tirado, Oscar M. ^{[7
]}

Schwentner, Raphaela ^{[1
]}

Picci, Piero ^{[8
]}

Flanagan, Adrienne M. ^{[9
]}

Berg, Verena ^{[1
]}

Strauss, Sandra J. ^{[9
]}

Scotlandi, Katia ^{[8
]}

Lawlor, Elizabeth R. ^{[10
,11
]}

Snaar-Jagalska, Ewa ^{[3
,4
]}

Llombart-Bosch, Antonio ^{[5
]}

Kovar, Heinrich ^{[1
,2
]}

机构：

[1] Childrens Canc Res Inst, A-1090 Vienna, Austria

[2] Med Univ Vienna, Dept Pediat, Vienna, Austria

[3] Leiden Univ, Inst Biol, Leiden, Netherlands

[4] Leiden Univ, Dept Pathol, Leiden, Netherlands

[5] Univ Med Sch, Dept Pathol, Valencia, Spain

[6] Dana Farber Canc Inst, Boston, MA 02115 USA

[7] Hosp Llobregat, Inst Invest Biomed Bellvitge IDIBEL, Lab Oncol Mol, Barcelona, Spain

[8] Rizzoli Inst, Lab Expt Oncol, Bologna, Italy

[9] UCL, Inst Canc, London, England

[10] Univ Michigan, Translat Oncol Program, Dept Pediat, Ann Arbor, MI 48109 USA

[11] Univ Michigan, Translat Oncol Program, Dept Pathol, Ann Arbor, MI 48109 USA

来源：

CANCER RESEARCH | 2014年 / 74卷 / 22期

基金：

奥地利科学基金会;

关键词：

TRANSCRIPTIONAL ACTIVITY; REGULATES SIRT1; CELL-SURVIVAL; P53; PHOSPHORYLATION; ACETYLATION; TARGET; ACTIVATION; EXPRESSION;

D O I：

10.1158/0008-5472.CAN-14-1736

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：6578 / 6588

页数：11

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[1]

Hsa-mir-145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing's sarcoma [J].