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SLFN11 is widely expressed in pediatric sarcoma and induces variable sensitization to 1 replicative stress caused by DNA damaging agents

ABSTRACT: Schlafen family member 11 (SLFN11) increases sensitivity to replicative stress and has been proposed as a biomarker to predict sensitivity to DNA damaging agents (DDA). However, the role of SLFN11 in pediatric cancer has not been well explored. In this study, we found that protein expression strongly correlated with response to the PARP inhibitor talazoparib and the topoisomerase I inhibitor irinotecan in sarcoma cell lines, with SLFN11 knockout resulting in significant loss of sensitivity in vitro and in vivo. However, in contrast to its activity in adult tumors, high SLFN11 expression did not correlate with favorable outcome in a retrospective study of children with sarcoma. Our work suggests that the potential of SLFN11 to act as a biomarker may be limited to certain tumor backgrounds or contexts, and that impaired apoptotic response may be one targetable mechanism of resistance to DDA-induced replicative stress

ORGANISM(S): Homo sapiens

PROVIDER: GSE181094 | GEO | 2022/04/08

REPOSITORIES: GEO

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SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in high-grade serous ovarian cancer

Project description:Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDA), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens prior platinum-based chemotherapy treatment, we show, for the first time, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 is associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in a SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated, immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer-cell-intrinsic functional dispositions associated with sensitivity to DDA treatment.

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Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress [microarray]

Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.

2020-01-17 | GSE140175 | GEO

Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress [RNA-seq_CPT]

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Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress [ATAC-seq_CPTO]

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Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress [ATAC-seq_CHPTCHK1i]

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Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress [RNA-seq_CHK1i]

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Epigenetic Inactivation of the Putative DNA/RNA Helicase SLFN11 in Human Cancer Confers Resistance to Platinum-derived Drugs

Project description:Platinum-derived drugs such as cisplatin and carboplatin are among the most commonly used cancer chemotherapy drugs, but very few specific molecular and cellular markers to predict different sentivity to these agents in a given tumor type have been clearly identified. Because epigenetic gene silencing is increasingly being recognized as a factor in conferring distinct tumoral drug sensitivity, we have used a comprehensive DNA methylation microarray platform to interrogate the widely characterized NCI60 panel of human cancer cell lines according to CpG methylation status and cisplatin/carboplatin sensitivity. Using this approach, we have identified that promoter CpG island hypermethylation-associated silencing of the putative DNA/RNA helicase Schlafen-11 (SLFN11) is associated with increased resistance to platinum-derived compounds. We have also experimentally validated these findings in vitro. In this setting, we were also able to identify the BRCA1 interacting DHX9 RNA helicase (also known as RHA) as a protein partner for SLFN11, suggesting a mechanistic pathway for the observed chemoresistance effect. Most importantly, we were able to extend these findings to the clinical setting where we observed that those patients with ovarian and non-small cell lung cancer carrying SLFN11 hypermethylation showed poor response to cisplatin and carboplatin treatments. Overall, these results identify SLFN11 epigenetic inactivation as a predictor of resistance to platin-derived drugs in human cancer.

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Critical regulatory roles of SLFN11 on NF-kB signaling and its effects on glioblastoma growth and survival

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