Dataset Information

Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma.

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.

SUBMITTER: Patel PO

PROVIDER: S-EPMC6570473 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma.

Patel Priyal O PO Pishas Kathleen I KI Taslim Cenny C Selich-Anderson Julia J Theisen Emily R ER Lessnick Stephen L SL

Oncotarget 20190611 39

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 o ...[more]

PMID: 31231465

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Project description:MicroRNAs (miRs) have been identified as potent regulators of both normal development and the hallmarks of cancer. Targeting of microRNAs has been shown to have preclinical promise, and select miR-based therapies are now in clinical trials. Ewing Sarcoma is a biologically aggressive pediatric cancer with little change in clinical outcomes despite improved chemotherapeutic regimens. There is a substantial need for new therapies to improve Ewing Sarcoma outcomes and to prevent chemotherapy-related secondary sequelae. Most Ewing Sarcoma tumors are driven by the EWS/Fli-1 fusion oncoprotein, acting as a gain-of-function transcription factor causing dysregulation of a variety of targets, including microRNAs. Our previous studies, and those of others, have identified upregulation of miRs belonging to the related miR-17~92a, miR-106b~25, and miR-106a~363 clusters in Ewing Sarcoma. However, the functional consequences of this have not been characterized, nor has miR blockade been explored as an anti-cancer strategy in Ewing Sarcoma. To simulate a potential therapeutic approach, we examined the effects of blockade of these clusters, and their component miRs. Using colony formation as a read-out, we find that blockade of selected individual cluster component miRs, using specific inhibitors, has little or no effect. Combinatorial inhibition using miR "sponge" methodology, on the other hand, is inhibitory to colony formation, with blockade of whole clusters generally more effective than blockade of miR families. We show that a miR-blocking sponge directed against the poorly characterized miR-106a~363 cluster is a particularly potent inhibitor of clonogenic growth in a subset of Ewing Sarcoma cell lines. We further identify upregulation of miR-15a as a downstream mechanism contributing to the miR-106a~363 sponge growth-inhibitory effect. Taken together, our studies provide support for a pro-oncogenic role of the miR-106a~363 cluster in Ewing Sarcoma, and identify miR-106a~363 blockade, as well as miR-15a replacement, as possible strategies for inhibition of Ewing Sarcoma growth.

Dataset Information

Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma.

Publications

Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma.

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