title: RORα binds to E2F1 to inhibit cell proliferation and regulate mammary gland branching morphogenesis.
abstract: Retinoic acid receptor-related orphan nuclear receptor alpha (RORα) is a potent tumor suppressor that reduces cell proliferation and inhibits tumor growth. However, the molecular mechanism by which it inhibits cell proliferation remains unknown. We demonstrate a noncanonical nuclear receptor pathway in which RORα binds to E2F1 to inhibit cell cycle progression. We showed that RORα bound to the heptad repeat and marked box region of E2F1 and suppressed E2F1-regulated transcription in epithelial cells. Binding of RORα inhibited E2F1 acetylation and its DNA-binding activity by recruiting histone deacetylase 1 (HDAC1) to the protein complexes. Knockdown of HDAC1 or inhibition of HDAC activity at least partially rescued transcription factor activity of E2F1 that was repressed by RORα. Importantly, RORα levels were increased in mammary ducts compared to terminal end buds and inversely correlated with expression of E2F1 target genes and cell proliferation. Silencing RORα in mammary epithelial cells significantly enhanced cell proliferation in the ductal epithelial cells and promoted side branching of the mammary ducts. These results reveal a novel link between RORα and E2F1 in regulating cell cycle progression and mammary tissue morphogenesis.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Xiong
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA ren.xu2010@uky.edu.
authors.forename: Ren
authors.initials: R
authors.lastname: Xu
mesh_terms: D000107:Acetylation; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000254:growth & development*; D051379:Mice; D009024:Morphogenesis; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1