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

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, Lluis Morey, Tan A. Ince, Michael Johnson and Joyce M. Slingerland ()
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Seyedeh Fatemeh Razavipour: Georgetown University
Hyunho Yoon: University of Miami, Miller School of Medicine
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
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
Lluis Morey: University of Miami, Miller School of Medicine
Tan A. Ince: Weill Cornell Medicine
Michael Johnson: Georgetown University
Joyce M. Slingerland: Georgetown University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48742-y

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