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Title: SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
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
Saigí, Maria
Piulats, Josep M.
Matias-Guiu, Xavier
Medina, Pedro P.
Vidal, August
Villanueva Garatachea, Alberto
Sanchez Cespedes, Montse
Keywords: Càncer
Issue Date: 14-Jul-2021
Publisher: Springer Science and Business Media LLC
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: Nature Communications, 2021, vol. 12, num. 4319
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Appears in Collections:Publicacions de projectes de recerca finançats per la UE
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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