title: KDM4B is a master regulator of the estrogen receptor signalling cascade.
abstract: The 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.
authors.affiliation: Solid Tumour Target Discovery Group, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Newcastle Upon Tyne, NE2 4HH, UK. luke.gaughan@ncl.ac.uk
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Stockley
authors.forename: Kelly
authors.initials: K
authors.lastname: Coffey
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Neill
authors.forename: Dominic L
authors.initials: DL
authors.lastname: Jones
authors.forename: Mark
authors.initials: M
authors.lastname: Wade
authors.forename: Jamie
authors.initials: J
authors.lastname: Wright
authors.forename: Madeleine
authors.initials: M
authors.lastname: Moore
authors.forename: Sandy
authors.initials: S
authors.lastname: Tse
authors.forename: Lynsey
authors.initials: L
authors.lastname: Rogerson
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
mesh_terms: D002460:Cell Line; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism* / Q000502:physiology; D061986:MCF-7 Cells; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional; D015398:Signal Transduction
chemical_list: C496499:FOXA1 protein, human; D050990:GATA3 Transcription Factor; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D011960:Receptors, Estrogen; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human