LAUSR

Significance PI3K is activated in over 60% of human cancers, mediating C-terminal p27 phosphorylation. This work reveals cooperation between PI3K and cJun pathways: p27 phosphorylation by PI3K-activated kinases stimulates p27/cJun corecruitment to chromatin and activation of transcription programs of cell adhesion, motility, TGFB2, and epithelial–mesenchymal transformation to drive tumor progression. Prior analysis showed that high p27pT157 strongly associates with activated AKTpS273 and p90RSKpT359 in human breast cancers. These cancers also differentially express p27/cJun target genes and identify a poor prognostic group. In cancers, the cell cycle-restraining effects of p27 are lost through increased proteolysis and decreased translation. We reveal a previously unknown oncogenic action of p27, in which p27 acts as a cJun coactivator to drive oncogenic gene expression programs. p27 shifts from CDK inhibitor to oncogene when phosphorylated by PI3K effector kinases. Here, we show that p27 is a cJun coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. In breast and bladder cancer cells with high p27pT157pT198 or expressing a CDK-binding defective p27pT157pT198 phosphomimetic (p27CK−DD), cJun is activated and interacts with p27, and p27/cJun complexes localize to the nucleus. p27/cJun up-regulates TGFB2 to drive metastasis in vivo. Global analysis of p27 and cJun chromatin binding and gene expression shows that cJun recruitment to many target genes is p27 dependent, increased by p27 phosphorylation, and activates programs of epithelial–mesenchymal transformation and metastasis. Finally, human breast cancers with high p27pT157 differentially express p27/cJun-regulated genes of prognostic relevance, supporting the biological significance of the work.