SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to...

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Autores: Romero, Octavio A., Vilarrubi, Andrea, Alburquerque-Bejar, Juan J., Gomez, Antonio, Andrades, Alvaro, Trastulli, Deborah, Pros, Eva, Setien, Fernando, Verdura, Sara, Farré, Lourdes, Martín-Tejera, Juan F., Llabata, Paula, Oaknin, Ana, Saigi, Maria, Piulats, Josep Maria, Matias-Guiu, Xavier, Medina, Pedro P., Vidal, August, Villanueva, Alberto, Sanchez-Cespedes, Montse
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
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:10459.1/467687
Acceso en línea:https://doi.org/10.1038/s41467-021-24618-3
https://hdl.handle.net/10459.1/467687
Access Level:acceso abierto
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spelling SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockadeRomero, Octavio A.Vilarrubi, AndreaAlburquerque-Bejar, Juan J.Gomez, AntonioAndrades, AlvaroTrastulli, DeborahPros, EvaSetien, FernandoVerdura, SaraFarré, LourdesMartín-Tejera, Juan F.Llabata, PaulaOaknin, AnaSaigi, MariaPiulats, Josep MariaMatias-Guiu, XavierMedina, Pedro P.Vidal, AugustVillanueva, AlbertoSanchez-Cespedes, MontseDespite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockadeNature Research2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1038/s41467-021-24618-3https://hdl.handle.net/10459.1/467687reponame: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/10.1038/s41467-021-24618-3Nature Communications, 2021, vol. 12, article number 4319cc-by (c)The Authors, 2021Attribution 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:recercat.cat:10459.1/4676872026-05-29T05:05:01Z
dc.title.none.fl_str_mv SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
title SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
spellingShingle SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
Romero, Octavio A.
title_short SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
title_full SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
title_fullStr SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
title_full_unstemmed SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
title_sort SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
dc.creator.none.fl_str_mv Romero, Octavio A.
Vilarrubi, Andrea
Alburquerque-Bejar, Juan J.
Gomez, Antonio
Andrades, Alvaro
Trastulli, Deborah
Pros, Eva
Setien, Fernando
Verdura, Sara
Farré, Lourdes
Martín-Tejera, Juan F.
Llabata, Paula
Oaknin, Ana
Saigi, Maria
Piulats, Josep Maria
Matias-Guiu, Xavier
Medina, Pedro P.
Vidal, August
Villanueva, Alberto
Sanchez-Cespedes, Montse
author Romero, Octavio A.
author_facet Romero, Octavio A.
Vilarrubi, Andrea
Alburquerque-Bejar, Juan J.
Gomez, Antonio
Andrades, Alvaro
Trastulli, Deborah
Pros, Eva
Setien, Fernando
Verdura, Sara
Farré, Lourdes
Martín-Tejera, Juan F.
Llabata, Paula
Oaknin, Ana
Saigi, Maria
Piulats, Josep Maria
Matias-Guiu, Xavier
Medina, Pedro P.
Vidal, August
Villanueva, Alberto
Sanchez-Cespedes, Montse
author_role author
author2 Vilarrubi, Andrea
Alburquerque-Bejar, Juan J.
Gomez, Antonio
Andrades, Alvaro
Trastulli, Deborah
Pros, Eva
Setien, Fernando
Verdura, Sara
Farré, Lourdes
Martín-Tejera, Juan F.
Llabata, Paula
Oaknin, Ana
Saigi, Maria
Piulats, Josep Maria
Matias-Guiu, Xavier
Medina, Pedro P.
Vidal, August
Villanueva, Alberto
Sanchez-Cespedes, Montse
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
description Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
publishDate 2021
dc.date.none.fl_str_mv 2021
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://doi.org/10.1038/s41467-021-24618-3
https://hdl.handle.net/10459.1/467687
url https://doi.org/10.1038/s41467-021-24618-3
https://hdl.handle.net/10459.1/467687
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/10.1038/s41467-021-24618-3
Nature Communications, 2021, vol. 12, article number 4319
dc.rights.none.fl_str_mv cc-by (c)The Authors, 2021
Attribution 4.0 International
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c)The Authors, 2021
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv 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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