title: Retinoic acid impairs estrogen signaling in breast cancer cells by interfering with activation of LSD1 via PKA.
abstract: More than 70% of breast cancers in women require estrogens for cell proliferation and survival. 17β-estradiol (E2) effect on mammary target cells is almost exclusively mediated by its binding to the estrogen receptor-α (ERα) that joins chromatin where it assembles active transcription complexes. The proliferative and pro-survival action of estrogens is antagonized in most cases by retinoic acid (RA), even though the cognate retinoic acid receptor-α (RARα) cooperates with ERα on promoters of estrogen-responsive genes. We have examined at the molecular level the crosstalk between these nuclear receptors from the point of view of their control of cell growth and show here that RA reverts estrogen-stimulated transcription of the pivotal anti-apoptotic bcl-2 gene by preventing demethylation of dimethyl lysine 9 in histone H3 (HeK9me2). As we previously reported, this is obtained by means of E2-triggered activation of the lysine-specific demethylase 1 (LSD1), an enzyme that manages chromatin plasticity in order to allow specific movements of chromosomal regions within the nucleus. We find that E2 fuels LSD1 by inducing migration of the catalytic subunit of protein kinase A (PKA) into the nucleus, where it targets estrogen-responsive loci. RA rescues LSD1-dependent disappearance of H3K9me2 at bcl-2 regulatory regions upon the prevention of PKA assembly to the same sites.
authors.affiliation: Istituto di Scienze dell'Alimentazione, Avellino, Italy.
authors.forename: Maria Neve
authors.initials: MN
authors.lastname: Ombra
authors.forename: Annalisa
authors.initials: A
authors.lastname: Di Santi
authors.forename: Ciro
authors.initials: C
authors.lastname: Abbondanza
authors.forename: Antimo
authors.initials: A
authors.lastname: Migliaccio
authors.forename: Enrico Vittorio
authors.initials: EV
authors.lastname: Avvedimento
authors.forename: Bruno
authors.initials: B
authors.lastname: Perillo
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D020134:Catalytic Domain; D002843:Chromatin / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D008745:Methylation; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D002843:Chromatin; D004967:Estrogens; D005419:Flavonoids; D006657:Histones; D007546:Isoquinolines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; D005576:Colforsin; D014212:Tretinoin; D056466:Histone Demethylases; C495195:KDM1A protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one