The DNA damage response gene SLFN11 is a transcriptional target of ETS transcription factors in Ewing’s sarcoma and other cancers

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NCI	CANCER-21

* FARE Award Winner

Authors

• SW Tang
• S Bilke
• L Cao
• FG Sousa
• M Yamade
• J Murai
• V Rajapakse
• LJ Helmam
• PS Melzer
• Y Pommier

Abstract

Schlafen-11 (SLFN11) is a critical determinant of response of cancer cells to DNA-targeted therapies. Ewing’s sarcoma (EWS), which is characterized by expressing the chimeric transcription factor EWS-FLI1, has notably high SLFN11 expression. This led us to investigate whether EWS-FLI1 is causative for elevated SLFN11 expression. ChIP-Seq analysis of EWS-FLI1 in A673 EWS cells showed that EWS-FLI1 binds near the transcription start site of SLFN11. The results of promoter-luciferase reporter assays further demonstrate that EWS-FLI1 is a positive transcriptional regulator for SLFN11. Importantly, EWS-FLI1-mediated SLFN11 overexpression is responsible for high sensitivity of EWS cells to the topoisomerase I inhibitor camptothecin. The correlated expression between SLFN11 and FLI1 further extends to pediatric cancers, leukemia, breast cancer and prostate cancer. Correlation analysis of the gene expression profiles of cancer cell line panels from NCI-60 and the Cancer Cell Line Encyclopedia (CCLE) indicates that, in addition to FLI1, several ETS members including ETS1, may be involved in the regulation of SLFN11 expression. Together, this study suggests the emerging importance of SLFN11 for therapeutic response to DNA-damaging agents in ETS-related cancers.

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