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

Author

Listed:
  • Jeannine Diesch

    (Josep Carreras Leukaemia Research Institute (IJC)
    Germans Trias i Pujol Research Institute (PMPPC-IGTP))

  • 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
    German Cancer Consortium (DKTK), Partner Site Munich)

  • Michael Maher

    (Josep Carreras Leukaemia Research Institute (IJC))

  • Carolina Martínez Herráez

    (Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)
    Universitat de Barcelona)

  • Joan J. Bech-Serra

    (Josep Carreras Leukaemia Research Institute (IJC))

  • Michaela Fellner

    (Vienna BioCenter (VBC))

  • Philipp Rathert

    (Vienna BioCenter (VBC)
    University Stuttgart)

  • 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)
    Universitat de Barcelona)

  • Carolina de la Torre

    (Josep Carreras Leukaemia Research Institute (IJC))

  • Johannes Zuber

    (Vienna BioCenter (VBC)
    Medical University of Vienna, Vienna BioCenter (VBC))

  • Katharina S. Götze

    (Technische Universität München)

  • Marcus Buschbeck

    (Josep Carreras Leukaemia Research Institute (IJC)
    Germans Trias i Pujol Research Institute (PMPPC-IGTP))

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.

Suggested Citation

  • 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 Fellne, 2021. "Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26258-z
    DOI: 10.1038/s41467-021-26258-z
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    References listed on IDEAS

    as
    1. Joan Boyes & Peter Byfield & Yoshihiro Nakatani & Vasily Ogryzko, 1998. "Regulation of activity of the transcription factor GATA-1 by acetylation," Nature, Nature, vol. 396(6711), pages 594-598, December.
    2. Panagis Filippakopoulos & Jun Qi & Sarah Picaud & Yao Shen & William B. Smith & Oleg Fedorov & Elizabeth M. Morse & Tracey Keates & Tyler T. Hickman & Ildiko Felletar & Martin Philpott & Shonagh Munro, 2010. "Selective inhibition of BET bromodomains," Nature, Nature, vol. 468(7327), pages 1067-1073, December.
    3. Jason X. Cheng & Li Chen & Yuan Li & Adam Cloe & Ming Yue & Jiangbo Wei & Kenneth A. Watanabe & Jamile M. Shammo & John Anastasi & Qingxi J. Shen & Richard A. Larson & Chuan He & Michelle M. Beau & Ja, 2018. "RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    4. Philipp Rathert & Mareike Roth & Tobias Neumann & Felix Muerdter & Jae-Seok Roe & Matthias Muhar & Sumit Deswal & Sabine Cerny-Reiterer & Barbara Peter & Julian Jude & Thomas Hoffmann & Łukasz M. Bory, 2015. "Transcriptional plasticity promotes primary and acquired resistance to BET inhibition," Nature, Nature, vol. 525(7570), pages 543-547, September.
    5. Jason X. Cheng & Li Chen & Yuan Li & Adam Cloe & Ming Yue & Jiangbo Wei & Kenneth A. Watanabe & Jamile M. Shammo & John Anastasi & Qingxi J. Shen & Richard A. Larson & Chuan He & Michelle M. Beau & Ja, 2018. "Author Correction: RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia," Nature Communications, Nature, vol. 9(1), pages 1-1, December.
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    Cited by:

    1. Jayden Sterling & Jennifer R. Baker & Adam McCluskey & Lenka Munoz, 2023. "Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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