Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis
Autor: | Antonio Gentilella, Johannes Zuber, Marguerite-Marie Le Pannérer, Carolina De La Torre, Michael Maher, René Winkler, Carolina Martínez Herráez, Lurdes Zamora, Joan Josep Bech-Serra, Matthias Muhar, Nigel Brooks, Marcus Buschbeck, Katharina Götze, Michaela Fellner, Mark van der Garde, Philipp Rathert, Raquel Casquero, Jeannine Diesch |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Antimetabolites
Antineoplastic Science Azacitidine Regulator General Physics and Astronomy Decitabine Therapeutics Leukemia Myelomonocytic Acute Article Acute myeloid leukaemia General Biochemistry Genetics and Molecular Biology Small hairpin RNA Cell Line Tumor Hematopoesi medicine Protein biosynthesis Humans heterocyclic compounds CREB-binding protein neoplasms Multidisciplinary biology Chemistry RNA General Chemistry DNA Methylation Terapèutica CREB-Binding Protein Hematopoiesis stomatognathic diseases Histone Protein Biosynthesis biology.protein Cancer research Myelodysplastic syndrome medicine.drug |
Zdroj: | Nature Communications r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol instname Dipòsit Digital de la UB Universidad de Barcelona Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021) |
ISSN: | 2041-1723 |
Popis: | 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. Azacitidine (AZA) treatment is used for patients with myelodysplasias that cannot undergo bone marrow transplantation; however, AZA treatment is only partially effective. Here the authors show synergy of AZA with compounds inhibiting the chromatin regulators CBP and p300, which is mediated by the RNA-dependent functions of AZA affecting protein translation. |
Databáze: | OpenAIRE |
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