SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Sai-Wen TangYves Pommier

Abstract

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 SLFN11 is regulated in cancer cells remained unknown. Ewing sarcoma, which is characterized by the chimeric transcription factor EWS-FLI1, has notably high SLFN11 expression, leading us to investigate whether EWS-FLI1 drives SLFN11 expression and the role of SLFN11 in the drug response of Ewing sarcoma cells. Binding sites of EWS-FLI1 on the SLFN11 promoter were analyzed by chromatin immunoprecipitation sequencing and promoter-luciferase reporter analyses. The relationship between SLFN11 and EWS-FLI1 were further examined in EWS-FLI1-knockdown or -overexpressing cells and in clinical tumor samples. EWS-FLI1 binds near the transcription start site of SLFN11 promoter and acts as a positive regulator of SLFN11 expression in Ewing sarcoma cells. EWS-FLI1-mediated SLFN11 expression is responsible for high sensitivity of Ewing sarcoma to camptothecin and combinations of PARP inhibitors with temozolomide. Importantly, Ewing sarcoma patients with higher SLFN11 expression showed better tumor-free survival rate. The correlated expression between SLFN11 and FLI1 e...Continue Reading

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