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Pàgina inicial > Articles > Articles publicats > SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade |
Data: | 2021 |
Resum: | 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. |
Ajuts: | European Commission. Horizon 2020 799850 Ministerio de Economía y Competitividad BES-2015-072204 Ministerio de Economía y Competitividad FPU17/00067 Ministerio de Economía y Competitividad IJCI-2016-28201 Ministerio de Economía y Competitividad PRE2018-084624 Agencia Estatal de Investigación SAF-2017-82186R Instituto de Salud Carlos III CM17/00180 Instituto de Salud Carlos III PI19/01320 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-364 |
Nota: | The authors thank Isabel Bartolessis (Cancer Genetics Group) at IJC for technical assistance. This work was supported by the Spanish Ministry of Economy and Competitivity-MINECO (grant number SAF-2017-82186R, to M.S.-C., and grant PI19/01320 to A. Villanueva) and from the Fundación Científica of the Asociación Española Contra el Cancer (AECC) (grant number GCB14142170MONT) to M.S.-C. A. Villanueva is also funded by the Department of Health of the Generalitat de Catalunya (2014SGR364). O.A. R. received a Juan de la Cierva postdoctoral contract (grant No. IJCI-2016-28201, until November 2019) and an AECC research contract (INVES19045ROME from December 2019). A. Vilarrubi, P.L. and A.A. are supported by pre-doctoral contracts from the Spanish MINECO (FPI-fellowship: PRE2018-084624, BES-2015-072204 and FPU17/ 00067). M.S. was supported by a Rio Hortega contract from the Instituto de Salud Carlos III (CM17/00180). L.F. received a European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions grant agreement, number 799850. |
Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | 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 |
Publicat a: | Nature communications, Vol. 12 Núm. 1 (january 2021) , p. 4319, ISSN 2041-1723 |
14 p, 5.6 MB |