Estrogen-dependent downregulation of hairy and enhancer of split homolog-1 gene expression in breast cancer cells is mediated via a 3' distal element.
Regulation of hairy and enhancer of split homologue-1 (HES-1) by estradiol and all-trans retinoic acid affects proliferation of human breast cancer cells. Here, we identify and characterize cis-regulatory elements involved in HES-1 regulation. In the distal 5' promoter of the HES-1 gene, we found a retinoic acid response element and in the distal 3' region, an estrogen receptor alpha(ER)alpha binding site. The ERalpha binding site, composed of an estrogen response element (ERE) and an ERE half-site, is important for both ERalpha binding and transcriptional regulation. Chromatin immunoprecipitation assays revealed that ERalpha is recruited to the ERE and associates with the HES-1 promoter. We also show recruitment of nuclear receptor co-regulators to the ERE in response to estradiol, followed by a decrease in histone acetylation and RNA polymerase II docking in the HES-1 promoter region. Our findings are consistent with a novel type of repressive estrogen response element in the distal 3' region of the HES-1 gene.
Müller
Patrick
P
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Merrell
Kenneth W
KW
Crofts
Justin D
JD
Rönnlund
Caroline
C
Lin
Chin-Yo
CY
Gustafsson
Jan-Ake
JA
Ström
Anders
A
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D013997:Time Factors; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006657:Histones; D018398:Homeodomain Proteins; D012319:RNA Polymerase II; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human