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MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing

Ewing sarcoma is a cancer of children and young adults characterized by the critical translocation-associated fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a...

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Autores principales: Vital, Tamara, Wali, Aminah, Butler, Kyle V., Xiong, Yan, Foster, Joseph P., Marcel, Shelsa S., McFadden, Andrew W., Nguyen, Valerie U., Bailey, Benton M., Lamb, Kelsey N., James, Lindsey I., Frye, Stephen V., Mosely, Amber L., Jin, Jian, Pattenden, Samantha G., Davis, Ian J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924231/
https://www.ncbi.nlm.nih.gov/pubmed/36793594
http://dx.doi.org/10.3389/fonc.2023.1099550
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author Vital, Tamara
Wali, Aminah
Butler, Kyle V.
Xiong, Yan
Foster, Joseph P.
Marcel, Shelsa S.
McFadden, Andrew W.
Nguyen, Valerie U.
Bailey, Benton M.
Lamb, Kelsey N.
James, Lindsey I.
Frye, Stephen V.
Mosely, Amber L.
Jin, Jian
Pattenden, Samantha G.
Davis, Ian J.
author_facet Vital, Tamara
Wali, Aminah
Butler, Kyle V.
Xiong, Yan
Foster, Joseph P.
Marcel, Shelsa S.
McFadden, Andrew W.
Nguyen, Valerie U.
Bailey, Benton M.
Lamb, Kelsey N.
James, Lindsey I.
Frye, Stephen V.
Mosely, Amber L.
Jin, Jian
Pattenden, Samantha G.
Davis, Ian J.
author_sort Vital, Tamara
collection PubMed
description Ewing sarcoma is a cancer of children and young adults characterized by the critical translocation-associated fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a model to interrogate mechanisms underlying chromatin dysregulation in tumorigenesis. Previously, we developed a high-throughput chromatin-based screening platform based on the de novo enhancers and demonstrated its utility in identifying small molecules capable of altering chromatin accessibility. Here, we report the identification of MS0621, a molecule with previously uncharacterized mechanism of action, as a small molecule modulator of chromatin state at sites of aberrant chromatin accessibility at EWSR1::FLI1-bound loci. MS0621 suppresses cellular proliferation of Ewing sarcoma cell lines by cell cycle arrest. Proteomic studies demonstrate that MS0621 associates with EWSR1::FLI1, RNA binding and splicing proteins, as well as chromatin regulatory proteins. Surprisingly, interactions with chromatin and many RNA-binding proteins, including EWSR1::FLI1 and its known interactors, were RNA-independent. Our findings suggest that MS0621 affects EWSR1::FLI1-mediated chromatin activity by interacting with and altering the activity of RNA splicing machinery and chromatin modulating factors. Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target allows for a direct approach to screen for unrecognized modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts.
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spelling pubmed-99242312023-02-14 MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing Vital, Tamara Wali, Aminah Butler, Kyle V. Xiong, Yan Foster, Joseph P. Marcel, Shelsa S. McFadden, Andrew W. Nguyen, Valerie U. Bailey, Benton M. Lamb, Kelsey N. James, Lindsey I. Frye, Stephen V. Mosely, Amber L. Jin, Jian Pattenden, Samantha G. Davis, Ian J. Front Oncol Oncology Ewing sarcoma is a cancer of children and young adults characterized by the critical translocation-associated fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a model to interrogate mechanisms underlying chromatin dysregulation in tumorigenesis. Previously, we developed a high-throughput chromatin-based screening platform based on the de novo enhancers and demonstrated its utility in identifying small molecules capable of altering chromatin accessibility. Here, we report the identification of MS0621, a molecule with previously uncharacterized mechanism of action, as a small molecule modulator of chromatin state at sites of aberrant chromatin accessibility at EWSR1::FLI1-bound loci. MS0621 suppresses cellular proliferation of Ewing sarcoma cell lines by cell cycle arrest. Proteomic studies demonstrate that MS0621 associates with EWSR1::FLI1, RNA binding and splicing proteins, as well as chromatin regulatory proteins. Surprisingly, interactions with chromatin and many RNA-binding proteins, including EWSR1::FLI1 and its known interactors, were RNA-independent. Our findings suggest that MS0621 affects EWSR1::FLI1-mediated chromatin activity by interacting with and altering the activity of RNA splicing machinery and chromatin modulating factors. Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target allows for a direct approach to screen for unrecognized modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts. Frontiers Media S.A. 2023-01-30 /pmc/articles/PMC9924231/ /pubmed/36793594 http://dx.doi.org/10.3389/fonc.2023.1099550 Text en Copyright © 2023 Vital, Wali, Butler, Xiong, Foster, Marcel, McFadden, Nguyen, Bailey, Lamb, James, Frye, Mosely, Jin, Pattenden and Davis https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Vital, Tamara
Wali, Aminah
Butler, Kyle V.
Xiong, Yan
Foster, Joseph P.
Marcel, Shelsa S.
McFadden, Andrew W.
Nguyen, Valerie U.
Bailey, Benton M.
Lamb, Kelsey N.
James, Lindsey I.
Frye, Stephen V.
Mosely, Amber L.
Jin, Jian
Pattenden, Samantha G.
Davis, Ian J.
MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing
title MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing
title_full MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing
title_fullStr MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing
title_full_unstemmed MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing
title_short MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing
title_sort ms0621, a novel small-molecule modulator of ewing sarcoma chromatin accessibility, interacts with an rna-associated macromolecular complex and influences rna splicing
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924231/
https://www.ncbi.nlm.nih.gov/pubmed/36793594
http://dx.doi.org/10.3389/fonc.2023.1099550
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