Suppression of Deacetylase SIRT1 Mediates Tumor-Suppressive NOTCH Response and Offers a Novel Treatment Option in Metastatic Ewing Sarcoma
Suppression of Deacetylase SIRT1 Mediates Tumor-Suppressive NOTCH Response and Offers a Novel Treatment Option in Metastatic Ewing Sarcoma
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DOI：
10.1158/0008-5472.can-14-1736
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发表时间：
2014-11-15
期刊：
影响因子：
11.2
通讯作者：
Kovar, Heinrich
中科院分区：
文献类型：
--
作者：
Ban, Jozef;Aryee, Dave N. T.;Kovar, Heinrich
由于致癌突变，发育受体 NOTCH 在各种人类癌症中发挥着重要作用。在这里，我们描述了一种 NOTCH 诱导的肿瘤抑制的新机制，涉及去乙酰化酶 SIRT1 的调节，为使用 SIRT1 抑制剂治疗因 SIRT1 过表达而失活的癌症提供了理论依据。在尤文肉瘤细胞中，NOTCH 信号传导被驱动癌基因 EWS-FLI1 消除。由于NOTCH效应子HEY1的激活，NOTCH信号传导的恢复导致生长停滞，直接抑制SIRT1，从而激活p53。这种肿瘤抑制机制在尤文肉瘤细胞、B 细胞肿瘤和人类角质形成细胞中得到了验证，其中 NOTCH 失调与致病有关。值得注意的是，SIRT1/2 抑制剂 Tenovin-6 在体外杀死尤文肉瘤细胞，并在已建立的斑马鱼异种移植模型中抑制肿瘤生长和扩散。使用免疫组织化学分析原发组织标本，我们发现 SIRT1 高表达与尤文肉瘤转移和不良预后相关。我们的研究结果表明了使用 SIRT1 抑制剂治疗尤文肉瘤患者转移性疾病的机制原理。 (C) 2014 年 AACR。
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.