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

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 ne...

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Autores principales: Patel, Priyal O., Pishas, Kathleen I., Taslim, Cenny, Selich-Anderson, Julia, Theisen, Emily R., Lessnick, Stephen L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570473/
https://www.ncbi.nlm.nih.gov/pubmed/31231465
http://dx.doi.org/10.18632/oncotarget.26988
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author Patel, Priyal O.
Pishas, Kathleen I.
Taslim, Cenny
Selich-Anderson, Julia
Theisen, Emily R.
Lessnick, Stephen L.
author_facet Patel, Priyal O.
Pishas, Kathleen I.
Taslim, Cenny
Selich-Anderson, Julia
Theisen, Emily R.
Lessnick, Stephen L.
author_sort Patel, Priyal O.
collection PubMed
description 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.
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spelling pubmed-65704732019-06-21 Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma Patel, Priyal O. Pishas, Kathleen I. Taslim, Cenny Selich-Anderson, Julia Theisen, Emily R. Lessnick, Stephen L. Oncotarget Research Paper 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. Impact Journals LLC 2019-06-11 /pmc/articles/PMC6570473/ /pubmed/31231465 http://dx.doi.org/10.18632/oncotarget.26988 Text en Copyright: © 2019 Patel et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Patel, Priyal O.
Pishas, Kathleen I.
Taslim, Cenny
Selich-Anderson, Julia
Theisen, Emily R.
Lessnick, Stephen L.
Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma
title Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma
title_full Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma
title_fullStr Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma
title_full_unstemmed Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma
title_short Investigating the role of LSD2 as an epigenetic regulator in Ewing sarcoma
title_sort investigating the role of lsd2 as an epigenetic regulator in ewing sarcoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570473/
https://www.ncbi.nlm.nih.gov/pubmed/31231465
http://dx.doi.org/10.18632/oncotarget.26988
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