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Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function

Author

Listed:
  • Manish Kumar

    (All India Institute of Medical Sciences (AIIMS))

  • David Molkentine

    (University of Pittsburgh, UPMC Hillman Cancer Center)

  • Jessica Molkentine

    (University of Pittsburgh, UPMC Hillman Cancer Center)

  • Kathleen Bridges

    (University of Texas, MD Anderson Cancer Center)

  • Tongxin Xie

    (University of Texas, MD Anderson Cancer Center)

  • Liangpeng Yang

    (University of Texas, MD Anderson Cancer Center)

  • Andrew Hefner

    (University of Pittsburgh, UPMC Hillman Cancer Center)

  • Meng Gao

    (University of Texas, MD Anderson Cancer Center)

  • Reshub Bahri

    (University of Pittsburgh, UPMC Hillman Cancer Center)

  • Annika Dhawan

    (University of Pittsburgh, UPMC Hillman Cancer Center)

  • Mitchell J. Frederick

    (Baylor College of Medicine)

  • Sahil Seth

    (University of Texas, MD Anderson Cancer Center)

  • Mohamed Abdelhakiem

    (University of Pittsburgh, UPMC Hillman Cancer Center)

  • Beth M. Beadle

    (Stanford University)

  • Faye Johnson

    (University of Texas, MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences)

  • Jing Wang

    (The University of Texas Graduate School of Biomedical Sciences
    University of Texas, MD Anderson Cancer Center)

  • Li Shen

    (University of Texas, MD Anderson Cancer Center)

  • Timothy Heffernan

    (University of Texas, MD Anderson Cancer Center)

  • Aakash Sheth

    (Baylor College of Medicine)

  • Robert L. Ferris

    (University of Pittsburgh, UPMC Hillman Cancer Center)

  • Jeffrey N. Myers

    (University of Texas, MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences)

  • Curtis R. Pickering

    (University of Texas, MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences)

  • Heath D. Skinner

    (University of Pittsburgh, UPMC Hillman Cancer Center)

Abstract

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.

Suggested Citation

  • Manish Kumar & David Molkentine & Jessica Molkentine & Kathleen Bridges & Tongxin Xie & Liangpeng Yang & Andrew Hefner & Meng Gao & Reshub Bahri & Annika Dhawan & Mitchell J. Frederick & Sahil Seth & , 2021. "Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26570-8
    DOI: 10.1038/s41467-021-26570-8
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    1. Swarnalatha Manickavinayaham & Renier Vélez-Cruz & Anup K. Biswas & Ella Bedford & Brianna J. Klein & Tatiana G. Kutateladze & Bin Liu & Mark T. Bedford & David G. Johnson, 2019. "E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Mahmoud Ghandi & Franklin W. Huang & Judit Jané-Valbuena & Gregory V. Kryukov & Christopher C. Lo & E. Robert McDonald & Jordi Barretina & Ellen T. Gelfand & Craig M. Bielski & Haoxin Li & Kevin Hu & , 2019. "Next-generation characterization of the Cancer Cell Line Encyclopedia," Nature, Nature, vol. 569(7757), pages 503-508, May.
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    1. Di Yu & Yingying Liang & Claudia Kim & Anbalagan Jaganathan & Donglei Ji & Xinye Han & Xuelan Yang & Yanjie Jia & Ruirui Gu & Chunyu Wang & Qiang Zhang & Ka Lung Cheung & Ming-Ming Zhou & Lei Zeng, 2023. "Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Ziad Ibrahim & Tao Wang & Olivier Destaing & Nicola Salvi & Naghmeh Hoghoughi & Clovis Chabert & Alexandra Rusu & Jinjun Gao & Leonardo Feletto & Nicolas Reynoird & Thomas Schalch & Yingming Zhao & Ma, 2022. "Structural insights into p300 regulation and acetylation-dependent genome organisation," Nature Communications, Nature, vol. 13(1), pages 1-23, December.

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