IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34024-y.html
   My bibliography  Save this article

Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer

Author

Listed:
  • Donglin Ding

    (Mayo Clinic College of Medicine and Science
    Mayo Clinic College of Medicine and Science)

  • Rongbin Zheng

    (Boston Children’s Hospital
    Harvard Medical School)

  • Ye Tian

    (Affiliated Hospital of Nanjing University of Chinese Medicine)

  • Rafael Jimenez

    (Mayo Clinic College of Medicine and Science)

  • Xiaonan Hou

    (Mayo Clinic College of Medicine and Science)

  • Saravut J. Weroha

    (Mayo Clinic College of Medicine and Science)

  • Liguo Wang

    (Mayo Clinic College of Medicine and Science)

  • Lei Shi

    (Mayo Clinic College of Medicine and Science
    Affiliated People’s Hospital of Hangzhou Medical College)

  • Haojie Huang

    (Mayo Clinic College of Medicine and Science
    Mayo Clinic College of Medicine and Science
    Mayo Clinic College of Medicine and Science)

Abstract

Bromodomain and extraterminal (BET) proteins including BRD4 play important roles in oncogenesis and immune inflammation. Here we demonstrate that cancer cells with loss of the retinoblastoma (RB) tumor suppressor became resistant to small molecule bromodomain inhibitors of BET proteins. We find that RB binds to bromodomain-1 (BD1) of BRD4, but binding is impeded by CDK4/6-mediated RB phosphorylation at serine-249/threonine-252 (S249/T252). ChIP-seq analysis shows RB knockdown increases BRD4 occupancy at genomic loci of genes enriched in cancer-related pathways including the GPCR-GNBIL-CREB axis. S249/T252-phosphorylated RB positively correlates with GNBIL protein level in prostate cancer patient samples. BET inhibitor resistance in RB-deficient cells is abolished by co-administration of CREB inhibitor. Our study identifies RB protein as a bona fide intrinsic inhibitor of BRD4 and demonstrates that RB inactivation confers resistance to small molecule BET inhibitors, thereby revealing a regulatory hub that converges RB upstream signaling onto BRD4 functions in diseases such as cancer.

Suggested Citation

  • Donglin Ding & Rongbin Zheng & Ye Tian & Rafael Jimenez & Xiaonan Hou & Saravut J. Weroha & Liguo Wang & Lei Shi & Haojie Huang, 2022. "Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34024-y
    DOI: 10.1038/s41467-022-34024-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34024-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-34024-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Irfan A. Asangani & Vijaya L. Dommeti & Xiaoju Wang & Rohit Malik & Marcin Cieslik & Rendong Yang & June Escara-Wilke & Kari Wilder-Romans & Sudheer Dhanireddy & Carl Engelke & Mathew K. Iyer & Xiaoju, 2014. "Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer," Nature, Nature, vol. 510(7504), pages 278-282, June.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Donglin Ding & Alexandra M. Blee & Jianong Zhang & Yunqian Pan & Nicole A. Becker & L. James Maher & Rafael Jimenez & Liguo Wang & Haojie Huang, 2023. "Gain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Zhao Wei & Song Wang & Yaning Xu & Wenzheng Wang & Fraser Soares & Musaddeque Ahmed & Ping Su & Tingting Wang & Elias Orouji & Xin Xu & Yong Zeng & Sujun Chen & Xiaoyu Liu & Tianwei Jia & Zhaojian Liu, 2023. "MYC reshapes CTCF-mediated chromatin architecture in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Reyaz ur Rasool & Caitlin M. O’Connor & Chandan Kanta Das & Mohammed Alhusayan & Brijesh Kumar Verma & Sehbanul Islam & Ingrid E. Frohner & Qu Deng & Erick Mitchell-Velasquez & Jaya Sangodkar & Aqila , 2023. "Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34024-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.