P27 transcriptionally coregulates cJun to drive programs of tumor progression

Hyunho Yoon, Minsoon Kim, Kibeom Jang, Miyoung Shin, Alexandra Besser, Xue Xiao, Dekuang Zhao, Seth A. Wander, Karoline Briegel, LLuis Morey, Andy Minn, Joyce M Slingerland

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7005-7014
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number14
DOIs
StatePublished - Apr 2 2019

Fingerprint

Phosphorylation
Cyclin-Dependent Kinase Inhibitor p27
Breast Neoplasms
Neoplasm Metastasis
Chromatin Assembly and Disassembly
Phosphatidylinositol 3-Kinases
Oncogenes
Urinary Bladder Neoplasms
Genes
Chromatin
Neoplasms
Phosphotransferases
Up-Regulation
Gene Expression

Keywords

  • CJun
  • EMT
  • P27
  • TGF-β2
  • Transcriptional regulation

ASJC Scopus subject areas

  • General

Cite this

P27 transcriptionally coregulates cJun to drive programs of tumor progression. / Yoon, Hyunho; Kim, Minsoon; Jang, Kibeom; Shin, Miyoung; Besser, Alexandra; Xiao, Xue; Zhao, Dekuang; Wander, Seth A.; Briegel, Karoline; Morey, LLuis; Minn, Andy; Slingerland, Joyce M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 14, 02.04.2019, p. 7005-7014.

Research output: Contribution to journalArticle

Yoon, Hyunho ; Kim, Minsoon ; Jang, Kibeom ; Shin, Miyoung ; Besser, Alexandra ; Xiao, Xue ; Zhao, Dekuang ; Wander, Seth A. ; Briegel, Karoline ; Morey, LLuis ; Minn, Andy ; Slingerland, Joyce M. / P27 transcriptionally coregulates cJun to drive programs of tumor progression. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 14. pp. 7005-7014.
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AU - Xiao, Xue

AU - Zhao, Dekuang

AU - Wander, Seth A.

AU - Briegel, Karoline

AU - Morey, LLuis

AU - Minn, Andy

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AB - 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.

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