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Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer

Author

Listed:
  • Jingyi Liu

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine
    National Cancer Institute-Frederick)

  • Zhibing Duan

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Weijie Guo

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Lei Zeng

    (Icahn School of Medicine at Mount Sinai
    Jilin University)

  • Yadi Wu

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Yule Chen

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Fang Tai

    (Southern Medical University
    Southern Medical University
    Southern Medical University)

  • Yifan Wang

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Yiwei Lin

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Qiang Zhang

    (Icahn School of Medicine at Mount Sinai
    Jilin University)

  • Yanling He

    (Southern Medical University
    Southern Medical University
    Southern Medical University)

  • Jiong Deng

    (Shanghai Jiao Tong University School of Medicine)

  • Rachel L. Stewart

    (University of Kentucky College of Medicine)

  • Chi Wang

    (University of Kentucky College of Medicine)

  • Pengnian Charles Lin

    (National Cancer Institute-Frederick)

  • Saghi Ghaffari

    (Icahn School of Medicine at Mount Sinai)

  • B. Mark Evers

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Suling Liu

    (Cancer Institute, Fudan University Shanghai Cancer Center)

  • Ming-Ming Zhou

    (Icahn School of Medicine at Mount Sinai)

  • Binhua P. Zhou

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine)

  • Jian Shi

    (University of Kentucky College of Medicine
    University of Kentucky College of Medicine
    Southern Medical University
    Southern Medical University)

Abstract

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer.

Suggested Citation

  • Jingyi Liu & Zhibing Duan & Weijie Guo & Lei Zeng & Yadi Wu & Yule Chen & Fang Tai & Yifan Wang & Yiwei Lin & Qiang Zhang & Yanling He & Jiong Deng & Rachel L. Stewart & Chi Wang & Pengnian Charles Li, 2018. "Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07258-y
    DOI: 10.1038/s41467-018-07258-y
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