title: H3K27 demethylation by JMJD3 at a poised enhancer of anti-apoptotic gene BCL2 determines ERα ligand dependency.
abstract: Chromatin represents a repressive barrier to the process of ligand-dependent transcriptional activity of nuclear receptors. Here, we show that H3K27 methylation imposes ligand-dependent regulation of the oestrogen receptor α (ERα)-dependent apoptotic response via Bcl-2 in breast cancer cells. The activation of BCL2 transcription is dependent on the simultaneous inactivation of the H3K27 methyltransferase, EZH2, and the demethylation of H3K27 at a poised enhancer by the ERα-dependent recruitment of JMJD3 in hormone-dependent breast cancer cells. We also provide evidence that this pathway is modified in cells resistant to anti-oestrogen (AE), which constitutively express BCL2. We show that the lack of H3K27 methylation at BCL2 regulatory elements due to the inactivation of EZH2 by the HER2 pathway leads to this constitutive activation of BCL2 in these AE-resistant cells. Our results describe a mechanism in which the epigenetic state of chromatin affects ligand dependency during ERα-regulated gene expression.
authors.affiliation: Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Svotelis
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bianco
authors.forename: Jason
authors.initials: J
authors.lastname: Madore
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Huppé
authors.forename: Alexei
authors.initials: A
authors.lastname: Nordell-Markovits
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gévry
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008024:Ligands; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D002843:Chromatin; D047628:Estrogen Receptor alpha; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D005982:Glutathione Transferase