Abstract
Ewing sarcoma is the second most common solid bone malignancy diagnosed in pediatric and young adolescent populations. Despite aggressive multi-modal treatment strategies, 5-year event-free survival remains at 75% for patients with localized disease and 20% for patients with metastases. Thus, the need for novel therapeutic options is imperative. Recent studies have focused on epigenetic misregulation in Ewing sarcoma development and potential new oncotargets for treatment. This project focused on the study of LSD2, a flavin-dependent histone demethylase found to be overexpressed in numerous cancers. We previously demonstrated that Ewing sarcoma cell lines are extremely susceptible to small molecule LSD1 blockade with SP-2509. Drug sensitivity correlated with the degree of LSD2 induction following treatment. As such, the purpose of this study was to determine the role of LSD2 in the epigenetic regulation of Ewing sarcoma, characterize genes regulated by LSD2, and examine the impact of SP-2509 drug treatment on LSD2 gene regulation. Genetic depletion (shRNA) of LSD2 significantly impaired oncogenic transformation with only a modest impact on proliferation. Transcriptional analysis of Ewing sarcoma cells following LSD2knockdown revealed modulation of genes primarily involved in metabolic regulation and nervous system development. Gene set enrichment analysis showed that SP-2509 does not impact LSD2 targeted genes. Although there are currently no small molecule agents that specifically target LSD2, our results support further investigations into agents that can inhibit this histone demethylase as a possible treatment for Ewing sarcoma.
Highlights
Ewing sarcoma is the second most common solid bone malignancy diagnosed in pediatric and young adolescent populations [1]
Lysine Specific Demethylase 1 (LSD1/KDM1A) is often www.oncotarget.com associated with the Nucleosome Remodeling and Deacetylase (NuRD) complex and in Ewing sarcoma is required to mediate the repressive function of EWS/ FLI
We investigated the function of LSD2 as an epigenetic regulator
Summary
Ewing sarcoma is the second most common solid bone malignancy diagnosed in pediatric and young adolescent populations [1]. It is characterized by the presence of a somatic translocation between the 5’ portion of EWSR1 on chromosome 22 with the 3’ portion of an ETS transcription factor [2]. Previous research has focused on defining key EWS/FLI protein interactions that regulate the expression of tumor suppressors and oncogenes. One such interaction is between EWS/FLI and the Nucleosome Remodeling and Deacetylase (NuRD) co-repressor complex [4]. LSD1 is crucial for Ewing sarcoma cell proliferation and oncogenic transformation both in vitro and in vivo [3, 5, 10]
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