Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program

Background Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadr...

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Autores: Jiménez, Carlos, Antonelli, Roberta, Nadal Ribelles, Mariona, Devis Jauregui, Laura, Latorre, Pablo, Solé, Carme, Masanas, Marc, Molero Valenzuela, Adrià, Soriano, Aroa, Sánchez de Toledo, Josep, Llobet Navas, David, Roma, Josep, Posas, Francesc, De Nadal, Eulàlia, Gallego, Soledad, Moreno, Lucas, Segura, Miguel F.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/189125
Acceso en línea:https://hdl.handle.net/2445/189125
Access Level:acceso abierto
Palabra clave:Càncer
Epigenètica
Cancer
Epigenetics
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spelling Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic programJiménez, CarlosAntonelli, RobertaNadal Ribelles, MarionaDevis Jauregui, LauraLatorre, PabloSolé, CarmeMasanas, MarcMolero Valenzuela, AdriàSoriano, AroaSánchez de Toledo, JosepLlobet Navas, DavidRoma, JosepPosas, FrancescDe Nadal, EulàliaGallego, SoledadMoreno, LucasSegura, Miguel F.CàncerEpigenèticaCancerEpigeneticsBackground Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.Springer Science and Business Media LLC2022202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion17 p.application/pdfhttps://hdl.handle.net/2445/189125Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/s12943-022-01643-4Molecular Cancer, 2022, vol. 21, núm. 1https://doi.org/10.1186/s12943-022-01643-4cc by (c) Jiménez, Carlos et al., 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1891252026-05-29T05:05:01Z
dc.title.none.fl_str_mv Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
title Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
spellingShingle Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
Jiménez, Carlos
Càncer
Epigenètica
Cancer
Epigenetics
title_short Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
title_full Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
title_fullStr Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
title_full_unstemmed Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
title_sort Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
dc.creator.none.fl_str_mv Jiménez, Carlos
Antonelli, Roberta
Nadal Ribelles, Mariona
Devis Jauregui, Laura
Latorre, Pablo
Solé, Carme
Masanas, Marc
Molero Valenzuela, Adrià
Soriano, Aroa
Sánchez de Toledo, Josep
Llobet Navas, David
Roma, Josep
Posas, Francesc
De Nadal, Eulàlia
Gallego, Soledad
Moreno, Lucas
Segura, Miguel F.
author Jiménez, Carlos
author_facet Jiménez, Carlos
Antonelli, Roberta
Nadal Ribelles, Mariona
Devis Jauregui, Laura
Latorre, Pablo
Solé, Carme
Masanas, Marc
Molero Valenzuela, Adrià
Soriano, Aroa
Sánchez de Toledo, Josep
Llobet Navas, David
Roma, Josep
Posas, Francesc
De Nadal, Eulàlia
Gallego, Soledad
Moreno, Lucas
Segura, Miguel F.
author_role author
author2 Antonelli, Roberta
Nadal Ribelles, Mariona
Devis Jauregui, Laura
Latorre, Pablo
Solé, Carme
Masanas, Marc
Molero Valenzuela, Adrià
Soriano, Aroa
Sánchez de Toledo, Josep
Llobet Navas, David
Roma, Josep
Posas, Francesc
De Nadal, Eulàlia
Gallego, Soledad
Moreno, Lucas
Segura, Miguel F.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer
Epigenètica
Cancer
Epigenetics
topic Càncer
Epigenètica
Cancer
Epigenetics
description Background Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/189125
url https://hdl.handle.net/2445/189125
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s12943-022-01643-4
Molecular Cancer, 2022, vol. 21, núm. 1
https://doi.org/10.1186/s12943-022-01643-4
dc.rights.none.fl_str_mv cc by (c) Jiménez, Carlos et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Jiménez, Carlos et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 17 p.
application/pdf
dc.publisher.none.fl_str_mv Springer Science and Business Media LLC
publisher.none.fl_str_mv Springer Science and Business Media LLC
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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