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C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer

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Listed:
  • Seyedeh Fatemeh Razavipour

    (Georgetown University
    University of Miami, Miller School of Medicine)

  • Hyunho Yoon

    (University of Miami, Miller School of Medicine
    The Catholic University of Korea)

  • Kibeom Jang

    (University of Miami, Miller School of Medicine)

  • Minsoon Kim

    (University of Miami, Miller School of Medicine)

  • Hend M. Nawara

    (Georgetown University)

  • Amir Bagheri

    (Georgetown University)

  • Wei-Chi Huang

    (Georgetown University)

  • Miyoung Shin

    (University of Miami, Miller School of Medicine
    Yale School of Medicine)

  • Dekuang Zhao

    (University of Miami, Miller School of Medicine)

  • Zhiqun Zhou

    (University of Miami, Miller School of Medicine)

  • Derek Boven

    (University of Miami, Miller School of Medicine)

  • Karoline Briegel

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Lluis Morey

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Tan A. Ince

    (Weill Cornell Medicine)

  • Michael Johnson

    (Georgetown University)

  • Joyce M. Slingerland

    (Georgetown University
    University of Miami, Miller School of Medicine)

Abstract

In many cancers, a stem-like cell subpopulation mediates tumor initiation, dissemination and drug resistance. Here, we report that cancer stem cell (CSC) abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistically, this arises through p27 co-recruitment with STAT3/CBP to gene regulators of CSC self-renewal including MYC, the Notch ligand JAG1, and ANGPTL4. p27pTpT/STAT3 also recruits a SIN3A/HDAC1 complex to co-repress the Pyk2 inhibitor, PTPN12. Pyk2, in turn, activates STAT3, creating a feed-forward loop increasing stem-like properties in vitro and tumor-initiating stem cells in vivo. The p27-activated gene profile is over-represented in STAT3 activated human breast cancers. Furthermore, mammary transgenic expression of phosphomimetic, cyclin-CDK-binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis, yielding hyperplasia and microinvasive cancers that can metastasize to liver, further supporting a role for p27pTpT in CSC expansion. Thus, p27pTpT interacts with STAT3, driving transcriptional programs governing stem cell expansion or maintenance in normal and cancer tissues.

Suggested Citation

  • Seyedeh Fatemeh Razavipour & Hyunho Yoon & Kibeom Jang & Minsoon Kim & Hend M. Nawara & Amir Bagheri & Wei-Chi Huang & Miyoung Shin & Dekuang Zhao & Zhiqun Zhou & Derek Boven & Karoline Briegel & Llui, 2024. "C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48742-y
    DOI: 10.1038/s41467-024-48742-y
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    References listed on IDEAS

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