학술논문
The H3K27me3-demethylase KDM6A is suppressed in breast cancer stem-like cells, and enables the resolution of bivalency during the mesenchymal-epithelial transition.
Document Type
Academic Journal
Author
Taube JH; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Department of Biology, Baylor University, Waco, Texas, USA.; Institute of Biomedical Sciences, Baylor University, Waco, Texas, USA.; Sphyris N; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Johnson KS; Department of Biology, Baylor University, Waco, Texas, USA.; Reisenauer KN; Department of Biology, Baylor University, Waco, Texas, USA.; Nesbit TA; Department of Biology, Baylor University, Waco, Texas, USA.; Joseph R; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Vijay GV; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Sarkar TR; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Department of Integrative Bioscience, Texas A & M University, College Station, Texas, USA.; Bhangre NA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Song JJ; Depatment of Statistical Science, Baylor University, Waco, Texas, USA.; Chang JT; Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Texas, USA.; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Texas, USA.; Lee MG; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Soundararajan R; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Mani SA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Source
Publisher: Impact Journals Country of Publication: United States NLM ID: 101532965 Publication Model: eCollection Cited Medium: Internet ISSN: 1949-2553 (Electronic) Linking ISSN: 19492553 NLM ISO Abbreviation: Oncotarget Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
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.
Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.