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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Detalles Bibliográficos
Autores: Romero, Octavio A.|||0000-0003-0229-6530, Vilarrubi, Andrea|||0000-0002-2930-3246, Alburquerque-Béjar, Juan Jos|||0000-0002-9022-124X, Gómez Moruno, Antonio|||0000-0001-5308-981X, Andrades, Álvaro, Trastulli, Deborah|||0000-0003-2407-3290, Pros, Eva|||0000-0002-2366-7866, Setien, Fernando|||0000-0002-4061-4635, Verdura, Sara|||0000-0001-8980-0423, Farre, Lourdes|||0000-0002-3168-1940, Martín-Tejera, Juan F., Llabata, Paula|||0000-0001-7733-6475, Oaknin, Ana|||0000-0002-3592-7194, Saigí, Maria|||0000-0001-5815-5388, Piulats, Josep M.|||0000-0002-3606-1724, Matías-Guiu, Xavier|||0000-0002-7201-6605, Medina, Pedro P., Vidal, August|||0000-0001-5727-2099, Villanueva, Alejandro|||0000-0001-5164-0006, Sánchez Céspedes, Montse|||0000-0002-6045-5627
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:270515
Acceso en línea:https://ddd.uab.cat/record/270515
https://dx.doi.org/urn:doi:10.1038/s41467-021-24618-3
Access Level:acceso abierto
Palabra clave:Animals
Antineoplastic Agents
Benzazepines
Cell Line, Tumor
Cell Survival
DNA Helicases
Drug Resistance, Neoplasm
Gene Expression
Histone Deacetylase Inhibitors
Histone Demethylases
Histones
Humans
Jumonji Domain-Containing Histone Demethylases
Mice
Neoplasms
Nuclear Proteins
Pyrimidines
Transcription Factors
Transcriptional Activation
Descripción
Sumario: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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