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http://purl.uniprot.org/citations/24963049http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/24963049http://www.w3.org/2000/01/rdf-schema#comment"

Purpose

Ewing sarcoma is a pediatric bone tumor that absolutely relies on the transcriptional activity of the EWS/ETS family of fusion oncoproteins. While the most common fusion, EWS/FLI, utilizes lysine-specific demethylase 1 (LSD1) to repress critical tumor suppressors, small-molecule blockade of LSD1 has not yet been thoroughly explored as a therapeutic approach for Ewing sarcoma. We therefore evaluated the translational potential of potent and specific LSD1 inhibition with HCI2509 on the transcriptional program of both EWS/FLI and EWS/ERG as well as the downstream oncogenic phenotypes driven by EWS/ETS fusions in both in vitro and in vivo models of Ewing sarcoma.

Experimental design

RNA-seq was used to compare the transcriptional profiles of EWS/FLI, EWS/ERG, and treatment with HCI2509 in both EWS/FLI- and EWS/ERG-containing cell lines. We then evaluated morphologic phenotypes of treated cells with immunofluorescence. The induction of apoptosis was evaluated using caspase-3/7 activation and TUNEL staining. Colony forming assays were used to test oncogenic transformation and xenograft studies with patient-derived cell lines were used to evaluate the effects of HCI2509 on tumorigenesis.

Results

HCI2509 caused a dramatic reversal of both the up- and downregulated transcriptional profiles of EWS/FLI and EWS/ERG accompanied by the induction of apoptosis and disruption of morphologic and oncogenic phenotypes modulated by EWS/FLI. Importantly, HCI2509 displayed single-agent efficacy in multiple xenograft models.

Conclusions

These data support epigenetic modulation with HCI2509 as a therapeutic strategy for Ewing sarcoma, and highlight a critical dual role for LSD1 in the oncogenic transcriptional activity of EWS/ETS proteins."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.org/dc/terms/identifier"doi:10.1158/1078-0432.ccr-14-0072"xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Sharma S."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Hoffman L.M."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Beckerle M.C."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Sankar S."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Lessnick S.L."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Bearss J."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Mulvihill T."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Sorna V."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/author"Theisen E.R."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/date"2014"xsd:gYear
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/name"Clin Cancer Res"xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/pages"4584-4597"xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/title"Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth."xsd:string
http://purl.uniprot.org/citations/24963049http://purl.uniprot.org/core/volume"20"xsd:string
http://purl.uniprot.org/citations/24963049http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/24963049
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