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.
Highlights
NOTCH signaling is an evolutionary conserved pathway involved in tissue patterning and cell specification during normal development
Because TP53 stability is largely regulated by posttranslational modifications (PTM), we hypothesized that HEY1 represses a TP53 interacting protein involved in the destabilization of TP53
Of 45 genes with relevance to TP53 modification [16,17,18], five fulfilled the criterion of being significantly suppressed in response to both HEY1 expression in TC252 and EWS-FLI1 silencing in all five tested Ewing sarcoma cell lines (Supplementary Table S1): PRKDC, encoding DNA-dependent protein kinase; YEATS4, whose product GAS41 is involved in dephosphorylation of TP53 Ser366 [19]; PPA1, stabilizing MDM4 and dephosphorylating TP53 at Ser15 [20, 21]; PPP2R5C, a component of protein phosphatase 2A dephosphorylating TP53 at various residues including Thr55, Ser37, and Ser46 [22,23,24], and SIRT1, a type III deacetylase known to target histone and non-histone proteins including TP53
Summary
NOTCH signaling is an evolutionary conserved pathway involved in tissue patterning and cell specification during normal development. It is initiated following interaction of a cell surface expressed ligand (JAG1, JAG2, DLL1, 3 and 4) with a transmembrane monomeric NOTCH receptor (NOTCH1–4). Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Upon translocation to the nucleus, NICD activates the transcription factor CSL. Oncogenic NOTCH pathway activation by mutation occurs in many cancers including T-cell leukemia and a variety of solid tumors including breast, colorectal, ovarian, and non–small cell lung cancers. The mechanisms of tumor-suppressive NOTCH signaling remain unknown
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