title: The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer.
abstract: Endocrine therapy has successfully been used to treat estrogen receptor (ER)-positive breast cancer, but this invariably fails with cancers becoming refractory to treatment. Emerging evidence has suggested that fluctuations in ER co-regulatory protein expression may facilitate resistance to therapy and be involved in breast cancer progression. To date, a small number of enzymes that control methylation status of histones have been identified as co-regulators of ER signalling. We have identified the histone H3 lysine 9 mono- and di-methyl demethylase enzyme KDM3A as a positive regulator of ER activity. Here, we demonstrate that depletion of KDM3A by RNAi abrogates the recruitment of the ER to cis-regulatory elements within target gene promoters, thereby inhibiting estrogen-induced gene expression changes. Global gene expression analysis of KDM3A-depleted cells identified gene clusters associated with cell growth. Consistent with this, we show that knockdown of KDM3A reduces ER-positive cell proliferation and demonstrate that KDM3A is required for growth in a model of endocrine therapy-resistant disease. Crucially, we show that KDM3A catalytic activity is required for both ER-target gene expression and cell growth, demonstrating that developing compounds which target demethylase enzymatic activity may be efficacious in treating both ER-positive and endocrine therapy-resistant disease.
authors.affiliation: Northen Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wade
authors.affiliation: Northen Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Jones
authors.affiliation: Northen Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Wilson
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Stockley
authors.affiliation: Northen Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Kelly
authors.initials: K
authors.lastname: Coffey
authors.affiliation: Northen Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.affiliation: Northen Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK luke.gaughan@ncl.ac.uk.
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism* / Q000502:physiology; D061986:MCF-7 Cells; D011960:Receptors, Estrogen / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction
chemical_list: D011960:Receptors, Estrogen; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human