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C-terminally phosphorylated p27 regulates STAT3 transcriptional activation, inducing gene programs driving mammary duct and cancer stem cell expansion

GSE233351 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2024/04/19 Platform GPL24676
Summary
While, p27 inhibits cell cycle in normal cells, in most cancers, p27 acquires oncogenic activities when phosphorylated by PI3K-activated kinases at T157 and T198 (p27pTpT). Mechanistically, these oncogenic functions of p27pTpT are poorly understood. Here, we show that p27pTpT promotes cancer stem cell (CSC) expansion through STAT3 both in vitro and in vivo. p27 phosphorylation increased STAT3 recruitment to chromatin to induce CSC self-renewal genes including MYC, the Notch ligand, JAG1, and ANGPTL4. We identify a feed-forward loop in which p27pTpT/STAT3 co-represses the Pyk2 inhibitor, PTPN12. Pyk2 in turn activates STAT3, driving CSCs expansion. p27pTpT is also shown to critically regulate mammary gland development. Mammary transgenic expression of phosphomimetic, cyclin-CDK binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis and hyperplasia, yielding primary and metastatic breast cancers. This supports a model in which p27pTpT co-regulates STAT3 to drive programs governing stem cell expansion or maintenance in normal and cancer tissues.
Published in
C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer
Razavipour SF, Yoon H, Jang K et al. · Nature communications 2024 · PMID 38886396 · doi:10.1038/s41467-024-48742-y
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Also filed as BioProject PRJNA975920 and SRA study SRP439399. Searching any of these in the dataset finder brings you back here.

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