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

Autor: Razavipour SF; Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA.; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA., Yoon H; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA.; Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon-si, South Korea., Jang K; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA., Kim M; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA., Nawara HM; Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA., Bagheri A; Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA., Huang WC; Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA., Shin M; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA.; Department of Pathology, Yale School of Medicine, New Haven, CT, USA., Zhao D; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA., Zhou Z; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA., Van Boven D; John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA., Briegel K; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA.; Department of Surgery, University of Miami, Miller School of Medicine, Miami, Fl, USA., Morey L; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA.; John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA., Ince TA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Johnson M; Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA., Slingerland JM; Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA. js4915@georgetown.edu.; Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA. js4915@georgetown.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jun 17; Vol. 15 (1), pp. 5152. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1038/s41467-024-48742-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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