Similar Datasets
Project description:Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n = 17; IC50 range, 81 -1,593 nmol/L), in contrast resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50 > 300 μmol/L). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Mol Cancer Ther; 17(9); 1902-16. ©2018 AACR.
| S-EPMC6201274 | biostudies-literature
Project description:The transcriptional profile of LSD1 knockdown in A673 Ewing sarcoma cells mirrors that of EWS/FLI knockdown and LSD1 small molecule inhibition (SP-2509)
2019-05-03 | GSE98786 | GEO
Project description:The purpose of this study was to define biomarkers of sensitivty and mechanisms of resistance to the KDM1A/LSD1 inhibtor SP-2509 (HCI-2509) in Ewing sarcoma cell lines. We report that regardless of drug sensitivity all cell lines engage the UPR and ER-stress response following treatment with SP-2509 resulting in apoptotic cytotoxicity. In addition hypersentsitive cell lines shared a common basal transcriptnomic profile, with hypersensitive cell lines signficantly inducing ETS1 which was not observed in sensitive cell lines.
2019-05-03 | GSE98785 | GEO
Project description:Therapeutic targeting of KDM1A/LSD1 in Ewing sarcoma engages the ER-stress response
| PRJNA386197 | ENA
Project description:Ewing sarcoma is the second most common solid bone malignancy diagnosed in pediatric and young adolescent populations. Despite global co-operative efforts, outcomes for patients with relapsed and refractory disease remains obstinately poor. It has become increasingly clear that disruption of the epigenome as a result of alterations in epigenetic regulators, plays a pivotal role in tumorigenesis. As such, this study investigated Ewing sarcoma mechanisms of acquired resistance to the small molecule reversible lysine specific demethylase (LSD1/KDM1A) inhibitor SP-2509. Surprisingly, whole exome sequencing analysis of our generated A673 SP-2509 drug resistant cell line revealed an absence of mutations in KDM1A. Compared to parental counterparts, SP-2509 drug resistant cells demonstrated decreased anchorage independent growth capacity, enhanced sensitivity to the HDAC inhibitors vorinostat/entinostat and a distinct transcriptional profile that was enriched for extracellular matrix proteins. SP-2509 drug resistant cells also exhibited elevated expression levels of the multi-drug resistance genes ABCB1, ABCC3, and ABBC5 and decreased expression of the transcriptional repressor RCOR1/CoREST. Following several months of SP-2509 withdrawal, low level SP-2509 resistance was still apparent (6.3 fold increase in IC50), with drug resistant cell populations maintaining their distinct transcriptional profile. Furthermore, compared to parental cells, washout drug resistant lines displayed equal sensitivity to the standard Ewing sarcoma chemotherapeutic agent's vincristine and doxorubicin. Together these findings indicate that resistance to SP-2509 is not fully reversible or driven by direct mutation in KDM1A.
| S-EPMC6284858 | biostudies-literature
Project description:Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to ?-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway.
| S-EPMC3824007 | biostudies-other
Project description:Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression. Importantly, we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines. To examine the clinical relevance of these findings, we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues, and this increased expression was significantly correlated with poor prognosis. Mechanistically, we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis, and cotargeting ER stress pathways increased this effect both in vitro and in vivo. Taken together, these findings provide compelling evidence that targeting LSD1, G9a, and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.
| S-EPMC9185438 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-12-26 | GSE118871 | GEO
Project description:The transcriptional profile of A673 parental, and SP-2509 drug resistant washout cells (4 and 6 months)
2018-12-26 | GSE118870 | GEO
Project description:The transcriptional profile of A673 parental and SP-2509 Drug resistant cells treated with DMSO and SP-2509 (2uM 48hrs)
2018-12-26 | GSE118864 | GEO