Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA278139 | ENA |
REPOSITORIES: ENA
Similar Datasets
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.
2015-11-30 | GSE66872 | GEO
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.
2021-07-13 | GSE179896 | GEO
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 | GSE140937 | GEO
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 | GSE140932 | GEO
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
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 | GSE140936 | GEO
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 | GSE140935 | GEO
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 | GSE140934 | GEO
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 | GSE140933 | GEO
Project description:Platinum-based chemotherapies are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a comprehensive, reproducible data resource comprised of dynamic (+/-carboplatin) proteomic/posttranslational modification and RNASeq profiles from HGSOC intra-patient cell line pairs derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed extensive responses to carboplatin and differential responses between sensitive and resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO is a candidate therapeutic target to overcome platinum resistance.
2022-01-04 | GSE163152 | GEO