C-terminally phosphorylated p27 drives cancer-promoting inflammation

Abstract p27 normally inhibits cell cycle progression and growth. In cancers, deregulated acts as an oncogene to promote metastasis when phosphorylated by PI3K-activated kinases at T157 T198 (p27pTpT). We showed p27pTpT transcriptionally co-activates cJun induces STAT3 activation. Here, we pursue the hypothesis that target genes expand cancer stem cells (CSC) inflammation. triple negative breast (TNBC) lines, increases properties, including sphere formation expression of transcription factors MYC, OCT4, NANOG, KLF4through STAT3. ChIP-seq/RNA-seq recruits gene promoters induce profiles p27/STAT3 co-target genes, MYCand JAG1, increase tumor-initiating (TISC) in vivo. This work revealed a novel role for driver CSC expansion. Since CSCs mediate treatment resistance, part, promoting inflammation, next tested if drives associate strongly with inflammatory pathways. ATAC-seq/ ChIP-seq increased chromatin accessibility co-recruit oncogenic, proinflammatory (IL-6, NF-κB/RELA, VEGFA)and mediators immune evasion. also activation, p65 (NF-κB subunit), IL-6 protein levels on WB, CCL2 secretion ELISA. Notably, both knockdown inhibition decreased p27pTpT-driven secretion. Together, these data indicate is C-terminally phosphorylated, it acquires oncogenic STAT3-driven expansion