Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis

Jeannine Diesch, Marguerite-Marie Le Pannérer, René Winkler, Raquel Casquero, Matthias Muhar, Mark van der Garde, Michael Maher, Carolina Martínez Herráez, Joan J. Bech-Serra, Michaela Fellner, Philipp Rathert, Nigel Brooks, Lurdes Zamora, Antonio Gentilella, Carolina de la Torre, Johannes Zuber, Katharina S. Götze and Marcus Buschbeck ()
Additional contact information
Jeannine Diesch: Josep Carreras Leukaemia Research Institute (IJC)
Marguerite-Marie Le Pannérer: Josep Carreras Leukaemia Research Institute (IJC)
René Winkler: Josep Carreras Leukaemia Research Institute (IJC)
Raquel Casquero: Josep Carreras Leukaemia Research Institute (IJC)
Matthias Muhar: Vienna BioCenter (VBC)
Mark van der Garde: Technische Universität München
Michael Maher: Josep Carreras Leukaemia Research Institute (IJC)
Carolina Martínez Herráez: Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)
Joan J. Bech-Serra: Josep Carreras Leukaemia Research Institute (IJC)
Michaela Fellner: Vienna BioCenter (VBC)
Philipp Rathert: Vienna BioCenter (VBC)
Nigel Brooks: CellCentric, Ltd, Chesterford Research Park
Lurdes Zamora: ICO Badalona‐Hospital Germans Trias I Pujol, Josep Carreras Leukemia Research Institute (IJC)
Antonio Gentilella: Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)
Carolina de la Torre: Josep Carreras Leukaemia Research Institute (IJC)
Johannes Zuber: Vienna BioCenter (VBC)
Katharina S. Götze: Technische Universität München
Marcus Buschbeck: Josep Carreras Leukaemia Research Institute (IJC)

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26258-z

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DOI: 10.1038/s41467-021-26258-z

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