Abstract
<div>Abstract<p><b>Purpose:</b> SLFN11 was identified as a critical determinant of response to DNA-targeted therapies by analyzing gene expression and drug sensitivity of NCI-60 and CCLE datasets. However, how <i>SLFN11</i> is regulated in cancer cells remained unknown. Ewing sarcoma, which is characterized by the chimeric transcription factor EWS-FLI1, has notably high <i>SLFN11</i> expression, leading us to investigate whether EWS-FLI1 drives <i>SLFN11</i> expression and the role of SLFN11 in the drug response of Ewing sarcoma cells.</p><p><b>Experimental Design:</b> Binding sites of EWS-FLI1 on the <i>SLFN11</i> promoter were analyzed by chromatin immunoprecipitation sequencing and promoter-luciferase reporter analyses. The relationship between <i>SLFN11</i> and EWS-FLI1 were further examined in EWS-FLI1-knockdown or -overexpressing cells and in clinical tumor samples.</p><p><b>Results:</b> EWS-FLI1 binds near the transcription start site of <i>SLFN11</i> promoter and acts as a positive regulator of <i>SLFN11</i> expression in Ewing sarcoma cells. EWS-FLI1–mediated <i>SLFN11</i> expression is responsible for high sensitivity of Ewing sarcoma to camptothecin and combinations of PARP inhibitors with temozolomide. Importantly, Ewing sarcoma patients with higher <i>SLFN11</i> expression showed better tumor-free survival rate. The correlated expression between <i>SLFN11</i> and <i>FLI1</i> extends to leukemia, pediatric, colon, breast, and prostate cancers. In addition, expression of other ETS members correlates with <i>SLFN11</i> in NCI-60 and CCLE datasets, and molecular experiments demonstrate that ETS1 acts as a positive regulator for <i>SLFN11</i> expression in breast cancer cells.</p><p><b>Conclusions:</b> Our results imply the emerging relevance of <i>SLFN11</i> as an ETS transcription factor response gene and for therapeutic response to topoisomerase I inhibitors and temozolomide–PARP inhibitor combinations in ETS-activated cancers. <i>Clin Cancer Res; 21(18); 4184–93. ©2015 AACR</i>.</p><p><i>See related commentary by Kovar, p. 4033</i></p></div>
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