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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 principales: 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 M., Matias-Guiu, Xavier, Medina, Pedro P., Vidal, August, Villanueva, Alberto, Sanchez-Cespedes, Montse
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280185/
https://www.ncbi.nlm.nih.gov/pubmed/34262032
http://dx.doi.org/10.1038/s41467-021-24618-3
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author 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 M.
Matias-Guiu, Xavier
Medina, Pedro P.
Vidal, August
Villanueva, Alberto
Sanchez-Cespedes, Montse
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 M.
Matias-Guiu, Xavier
Medina, Pedro P.
Vidal, August
Villanueva, Alberto
Sanchez-Cespedes, Montse
author_sort Romero, Octavio A.
collection PubMed
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.
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spelling pubmed-82801852021-07-23 SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade 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 M. Matias-Guiu, Xavier Medina, Pedro P. Vidal, August Villanueva, Alberto Sanchez-Cespedes, Montse Nat Commun Article 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. Nature Publishing Group UK 2021-07-14 /pmc/articles/PMC8280185/ /pubmed/34262032 http://dx.doi.org/10.1038/s41467-021-24618-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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 M.
Matias-Guiu, Xavier
Medina, Pedro P.
Vidal, August
Villanueva, Alberto
Sanchez-Cespedes, Montse
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
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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280185/
https://www.ncbi.nlm.nih.gov/pubmed/34262032
http://dx.doi.org/10.1038/s41467-021-24618-3
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