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| Home > Articles > Published articles > Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis |
| Home > Articles > Published articles > Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis |
(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Research Institute of Molecular Pathology (IMP). Vienna BioCenter (VBC)) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Universitat de Barcelona. Departament de Bioquímica i Fisiologia) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (University Stuttgart) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Universitat de Barcelona. Departament de Bioquímica i Fisiologia) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Medical University of Vienna. Vienna BioCenter (VBC)) (Technische Universität München) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
| Date: | 2021 |
| Abstract: | The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis. |
| Grants: | Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-305 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-01743 Agencia Estatal de Investigación RTI2018-094005-B-I00 Ministerio de Economía y Competitividad FJCI-2014-22983 Ministerio de Economía y Competitividad PIE16/00011 Ministerio de Economía y Competitividad SAF2017-84301-P Instituto de Salud Carlos III PT17/0019 |
| Note: | This project was supported by the FEDER/Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación through the grant PIE16/00011 RESPONSE (to M.B.), the European Research Council ERC-StG-336860 (to J.Z.), the grant Juan de la Cierva- Formación FJCI-2014-22983 (to J.D.), the grant Sara Borrell CD17/00084 (to J.D.), the Marie Skłodowska Curie Training network "ChroMe" H2020-MSCA-ITN-2015-675610 (to M.M.), the FPI predoctoral fellowship BES-2016-077251 (to M.M.L.P.), the SFB 1243 DFG (to K.S.G.), the Austrian Science Fund SFB-F4710 (to J.Z.) and the Deutsche José Carreras Leukämie Stiftung DJCLS 14R/2018 (to K.G. and M.B.). Research in the Buschbeck lab is further supported by the following grants: MINECO grant RTI2018-094005-B-I00 (to M.B.), the Marie Skłodowska Curie Training network 'INTERCEPT-MDS' H2020-MSCA-ITN-2015-953407 (to M.B. and K.S.G.); AGAUR 2017-SGR-305 (to M.B.) and Fundació La Marató de TV3 257/C/2019 (to M.B.). Research at IMP is supported by Boehringer Ingelheim, the Austrian Research Promotion Agency (Headquarter grant FFG-852936) and the Austrian Academy of Sciences. Research at the IJC is generously supported by the 'La Caixa' Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme/Generalitat de Catalunya. A.G. received funds by "Agencia Estatal de Investigación" (AEI) through the Plan Nacional "Excelencia" grant number SAF2017-84301-P, by the "Associación Española Contra el Cancer" (AECC) grant number LABAE20040GENT and by the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR01743. Proteomic analyses were performed in the IJC Proteomic Unit, which are part of Proteored PRB3 and are supported by grant PT17/0019 from the PE I + D + i 2013-2016, funded by ISCIII and ERDF. We thank Kaoru Tohyama for providing MDS-L cells, members of the Buschbeck lab, the RESPONSE network (PIE16/00011), Blanca Xicoy and Francesc Solé for valuable discussions. We thank the IJC Biobanking unit for sample preparation and storage, Bernat Cucurull from the IJC Proteomics unit for the ClickIT sample preparation, Marco Fernandez for advice and training in flow cytometry and all other staff of IJC and IGTP core facilities for excellent support. |
| Rights: | 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.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Published in: | Nature communications, Vol. 12 Núm. 1 (january 2021) , p. 6060, ISSN 2041-1723 |
