KDM4B is a master regulator of the estrogen receptor signalling cascade.
AffiliationSolid Tumour Target Discovery Group, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Newcastle Upon Tyne, NE2 4HH, UK, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4, Newark street, London, E1 2AT, UK, Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Catherine Cookson, Medical School, Framlington Place, Newcastle University, NE2 4HH, UK and Molecular Pathology Group, Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Wilmslow Road, M20 4BX, UK.
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AbstractThe importance of the estrogen receptor (ER) in breast cancer (BCa) development makes it a prominent target for therapy. Current treatments, however, have limited effectiveness, and hence the definition of new therapeutic targets is vital. The ER is a member of the nuclear hormone receptor superfamily of transcription factors that requires co-regulator proteins for complete regulation. Emerging evidence has implicated a small number of histone methyltransferase (HMT) and histone demethylase (HDM) enzymes as regulators of ER signalling, including the histone H3 lysine 9 tri-/di-methyl HDM enzyme KDM4B. Two recent independent reports have demonstrated that KDM4B is required for ER-mediated transcription and depletion of the enzyme attenuates BCa growth in vitro and in vivo. Here we show that KDM4B has an overarching regulatory role in the ER signalling cascade by controlling expression of the ER and FOXA1 genes, two critical components for maintenance of the estrogen-dependent phenotype. KDM4B interacts with the transcription factor GATA-3 in BCa cell lines and directly co-activates GATA-3 activity in reporter-based experiments. Moreover, we reveal that KDM4B recruitment and demethylation of repressive H3K9me3 marks within upstream regulatory regions of the ER gene permits binding of GATA-3 to drive receptor expression. Ultimately, our findings confirm the importance of KDM4B within the ER signalling cascade and as a potential therapeutic target for BCa treatment.
CitationKDM4B is a master regulator of the estrogen receptor signalling cascade. 2013, 41 (14):6892-6904 Nucleic Acids Res
JournalNucleic Acids Research
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