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Novel Mechanisms Whereby p27 Drives Tumor Progression in PI3K-Activated Cancers

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University of Miami Coral Gables United States

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p27 shifts from CDK inhibitor to oncogene when phosphorylated by PI3K effector kinases. We show p27 is a cJun co-regulator,whose assembly and chromatin association is governed by p27 phosphorylation. Cancer cells with high p27pT157pT198 or expressing a CDK-binding defective p27pT157pT198 phosphomimetic, p27CK-DD, cJun is activated, binds p27 and p27cJun complexes localize to the nucleus. p27cJun upregulates TGFB2 to drive metastasis in vivo. Global analysis shows p27cJun recruitment to chromatin is increased by p27 phosphorylation and activates programs of EMT and metastasis. Human breast cancers with high p27pT157 differentially express p27-cJun regulated genes of prognostic relevance, supporting the biological significance of the work. p27cJun also corepress pro-differentiation genes to increase cancer stem cells. In cancer cells with highp27pT157pT198 or phosphomimetic p27CK-DD, nearly half of p27cJun co-targets are repressed and these govern differentiation.PTPN12 was strongly downregulated though p27 and cJun recruitment of SIN3A, YY1, and HDAC1 to corepress this tumor suppressor gene, leading to increased sphere formation and tumor initiating cells. Upon PTPN12 loss, its substrate, PYK2, mediatesSTAT3 activation, increases spheres and ALDH1 activity and tumor initiating cells in vivo. Thus, p27-bound cJun represses differentiation genes and via PTPN12 repression, activates pathways that upregulate cancer initiating cells.

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Technical Report,15 Sep 2017,14 Sep 2018



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Approved For Public Release;

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