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- Title
C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer.
- Authors
Razavipour, Seyedeh Fatemeh; Yoon, Hyunho; Jang, Kibeom; Kim, Minsoon; Nawara, Hend M.; Bagheri, Amir; Huang, Wei-Chi; Shin, Miyoung; Zhao, Dekuang; Zhou, Zhiqun; Van Boven, Derek; Briegel, Karoline; Morey, Lluis; Ince, Tan A.; Johnson, Michael; Slingerland, Joyce M.
- 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. Cancer stem cells (CSCs) have important roles in tumour initiation, metastasis and treatment resistance. Here, the authors show that C-terminally phosphorylated p27, together with STAT3, mediates the transcriptional regulation of CSC expansion, increasing cancer formation and metastasis in preclinical breast cancer models.
- Subjects
CANCER stem cells; CANCER genes; HYPERPLASIA; REGULATOR genes; BREAST; STEM cells
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-48742-y