The H3K27me3-demethylase KDM6A is suppressed in breast cancer stem-like cells, and enables the resolution of bivalency during the mesenchymal-epithelial transition
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Joseph H. Taube1,3,4,*, Nathalie Sphyris1,*, Kelsey S. Johnson3, Keighley N. Reisenauer3, Taylor A. Nesbit3, Robiya Joseph1, Geraldine V. Vijay1, Tapasree R. Sarkar1,5, Neeraja A. Bhangre1, Joon Jin Song6, Jeffrey T. Chang7,8, Min Gyu Lee9,10, Rama Soundararajan1 and Sendurai A. Mani1,2
1Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3Department of Biology, Baylor University, Waco, Texas, USA
4Institute of Biomedical Sciences, Baylor University, Waco, Texas, USA
5Department of Integrative Bioscience, Texas A & M University, College Station, Texas, USA
6Depatment of Statistical Science, Baylor University, Waco, Texas, USA
7Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Texas, USA
8Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Texas, USA
9Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
10Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Sendurai A. Mani, email: [email protected]
Joseph H. Taube, email: [email protected]
Keywords: epithelial-mesenchymal transition, mesenchymal-epithelial transition, KDM6A, bivalent genes, GSK-J4
Received: July 20, 2016 Accepted: April 26, 2017 Published: July 10, 2017
The deposition of the activating H3K4me3 and repressive H3K27me3 histone modifications within the same promoter, forming a so-called bivalent domain, maintains gene expression in a repressed but transcription-ready state. We recently reported a significantly increased incidence of bivalency following an epithelial-mesenchymal transition (EMT), a process associated with the initiation of the metastatic cascade. The reverse process, known as the mesenchymal-epithelial transition (MET), is necessary for efficient colonization. Here, we identify numerous genes associated with differentiation, proliferation and intercellular adhesion that are repressed through the acquisition of bivalency during EMT, and re-expressed following MET. The majority of EMT-associated bivalent domains arise through H3K27me3 deposition at H3K4me3-marked promoters. Accordingly, we show that the expression of the H3K27me3-demethylase KDM6A is reduced in cells that have undergone EMT, stem-like subpopulations of mammary cell lines and stem cell-enriched triple-negative breast cancers. Importantly, KDM6A levels are restored following MET, concomitant with CDH1/E-cadherin reactivation through H3K27me3 removal. Moreover, inhibition of KDM6A, using the H3K27me3-demethylase inhibitor GSK-J4, prevents the re-expression of bivalent genes during MET. Our findings implicate KDM6A in the resolution of bivalency accompanying MET, and suggest KDM6A inhibition as a viable strategy to suppress metastasis formation in breast cancer.
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