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

doi:10.1073/pnas.1817415116

p27 transcriptionally coregulates cJun to drive programs of tumor progression

Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7005-7014. doi: 10.1073/pnas.1817415116. Epub 2019 Mar 15.

Authors

Hyunho Yoon¹, Minsoon Kim^{1

2}, Kibeom Jang^{1

2}, Miyoung Shin¹, Alexandra Besser^{1

3}, Xue Xiao⁴, Dekuang Zhao¹, Seth A Wander¹, Karoline Briegel^{1

5}, Lluis Morey^{1

6

7}, Andy Minn^{8

9}, Joyce M Slingerland^{10

2

3

6

11}

Affiliations

¹ Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136.
² Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136.
³ Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136.
⁴ Bioinformatics Core, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136.
⁵ Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136.
⁶ Cancer Epigenetics Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136.
⁷ Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136.
⁸ Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
⁹ Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
¹⁰ Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; jslingerland@med.miami.edu.
¹¹ Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136.

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.

Keywords: EMT; TGF-β2; cJun; p27; transcriptional regulation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Adhesion
Cell Line, Tumor
Cell Movement*
Cyclin-Dependent Kinase Inhibitor p27 / genetics
Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
Epithelial-Mesenchymal Transition*
Gene Expression Regulation, Neoplastic*
Humans
Neoplasms / genetics
Neoplasms / metabolism*
Neoplasms / pathology
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-jun / genetics
Proto-Oncogene Proteins c-jun / metabolism*

Substances

CDKN1B protein, human
Proto-Oncogene Proteins c-jun
Cyclin-Dependent Kinase Inhibitor p27
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt

Abstract

Publication types

MeSH terms

Substances

Grants and funding