SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug responsein Ewing sarcoma

Sai Wen Tang, Sven Bilke, Liang Cao, Junko Murai, Fabricio G. Sousa, Mihoko Yamade, Vinodh Rajapakse, Sudhir Varma, Lee J. Helman, Javed Khan, Paul S. Meltzer, Yves Pommier

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Experimental Design: 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. Results: 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 extends to leukemia, pediatric, colon, breast, and prostate cancers. In addition, expression of other ETS members correlates with SLFN11 in NCI-60 and CCLE datasets, and molecular experiments demonstrate that ETS1 acts as a positive regulator for SLFN11 expression in breast cancer cells. Conclusions: Our results imply the emerging relevance of SLFN11 as an ETS transcription factor response gene and for therapeutic response to topoisomerase I inhibitors and temozolomide-PARP inhibitor combinations in ETS-activated cancers.

Original languageEnglish (US)
Pages (from-to)4184-4193
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number18
DOIs
StatePublished - Sep 15 2015
Externally publishedYes

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Ewing's Sarcoma
temozolomide
Pharmaceutical Preparations
Neoplasms
Transcription Factors
Topoisomerase I Inhibitors
Breast Neoplasms
Camptothecin
Chromatin Immunoprecipitation
Transcription Initiation Site
EWS-FLI fusion protein
Luciferases
Genetic Therapy
Colonic Neoplasms
Prostatic Neoplasms
Leukemia
Research Design
Survival Rate
Binding Sites
Pediatrics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tang, S. W., Bilke, S., Cao, L., Murai, J., Sousa, F. G., Yamade, M., ... Pommier, Y. (2015). SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug responsein Ewing sarcoma. Clinical Cancer Research, 21(18), 4184-4193. https://doi.org/10.1158/1078-0432.CCR-14-2112

SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug responsein Ewing sarcoma. / Tang, Sai Wen; Bilke, Sven; Cao, Liang; Murai, Junko; Sousa, Fabricio G.; Yamade, Mihoko; Rajapakse, Vinodh; Varma, Sudhir; Helman, Lee J.; Khan, Javed; Meltzer, Paul S.; Pommier, Yves.

In: Clinical Cancer Research, Vol. 21, No. 18, 15.09.2015, p. 4184-4193.

Research output: Contribution to journalArticle

Tang, SW, Bilke, S, Cao, L, Murai, J, Sousa, FG, Yamade, M, Rajapakse, V, Varma, S, Helman, LJ, Khan, J, Meltzer, PS & Pommier, Y 2015, 'SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug responsein Ewing sarcoma', Clinical Cancer Research, vol. 21, no. 18, pp. 4184-4193. https://doi.org/10.1158/1078-0432.CCR-14-2112
Tang, Sai Wen ; Bilke, Sven ; Cao, Liang ; Murai, Junko ; Sousa, Fabricio G. ; Yamade, Mihoko ; Rajapakse, Vinodh ; Varma, Sudhir ; Helman, Lee J. ; Khan, Javed ; Meltzer, Paul S. ; Pommier, Yves. / SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug responsein Ewing sarcoma. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 18. pp. 4184-4193.
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abstract = "Purpose: 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. Experimental Design: 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. Results: 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 extends to leukemia, pediatric, colon, breast, and prostate cancers. In addition, expression of other ETS members correlates with SLFN11 in NCI-60 and CCLE datasets, and molecular experiments demonstrate that ETS1 acts as a positive regulator for SLFN11 expression in breast cancer cells. Conclusions: Our results imply the emerging relevance of SLFN11 as an ETS transcription factor response gene and for therapeutic response to topoisomerase I inhibitors and temozolomide-PARP inhibitor combinations in ETS-activated cancers.",
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T1 - SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug responsein Ewing sarcoma

AU - Tang, Sai Wen

AU - Bilke, Sven

AU - Cao, Liang

AU - Murai, Junko

AU - Sousa, Fabricio G.

AU - Yamade, Mihoko

AU - Rajapakse, Vinodh

AU - Varma, Sudhir

AU - Helman, Lee J.

AU - Khan, Javed

AU - Meltzer, Paul S.

AU - Pommier, Yves

PY - 2015/9/15

Y1 - 2015/9/15

N2 - Purpose: 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. Experimental Design: 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. Results: 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 extends to leukemia, pediatric, colon, breast, and prostate cancers. In addition, expression of other ETS members correlates with SLFN11 in NCI-60 and CCLE datasets, and molecular experiments demonstrate that ETS1 acts as a positive regulator for SLFN11 expression in breast cancer cells. Conclusions: Our results imply the emerging relevance of SLFN11 as an ETS transcription factor response gene and for therapeutic response to topoisomerase I inhibitors and temozolomide-PARP inhibitor combinations in ETS-activated cancers.

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