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’s sarcoma (ES), 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 ES cells. Experimental Design Binding sites of EWS-FLI1 on the SLFN11 promoter were analyzed by chromatin immunoprecipitation-DNA sequence (ChIP-Seq) 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 ES cells. EWS-FLI1-mediated SLFN11 expression is responsible for high sensitivity of ES to camptothecin and combinations of PARP inhibitors with temozolomide. Importantly, ES 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.

Highlights d Upon replication stress, SLFN11 induces genome-wide accessibility at promoters d SLFN11 selectively activates the transcription of the immediate early genes (IEGs) d The putative ATPase and helicase activity is required for the functions of SLFN11

BackgroundHuman T-cell Leukemia Virus type 1 (HTLV-1) infects 20 million individuals world-wide and causes Adult T-cell Leukemia/Lymphoma (ATLL), a highly aggressive T-cell cancer. ATLL is refractory to treatment with conventional chemotherapy and fewer than 10% of afflicted individuals survive more than 5 years after diagnosis. HTLV-1 encodes a viral oncoprotein, Tax, that functions in transforming virus-infected T-cells into leukemic cells. All ATLL cases are believed to have reduced p53 activity although only a minority of ATLLs have genetic mutations in their p53 gene. It has been suggested that p53 function is inactivated by the Tax protein.ResultsUsing genetically altered mice, we report here that Tax expression does not achieve a functional equivalence of p53 inactivation as that seen with genetic mutation of p53 (i.e. a p53−/− genotype). Thus, we find statistically significant differences in tumorigenesis between Tax+p53+/+versus Tax+p53−/− mice. We also find a role contributed by the cellular Wip1 phosphatase protein in tumor formation in Tax transgenic mice. Notably, Tax+Wip1−/− mice show statistically significant reduced prevalence of tumorigenesis compared to Tax+Wip1+/+ counterparts.ConclusionsOur findings provide new insights into contributions by p53 and Wip1 in the in vivo oncogenesis of Tax-induced tumors in mice.