title: SOX9 mediates the retinoic acid-induced HES-1 gene expression in human breast cancer cells.
abstract: We have previously shown that the anti-proliferative effect of retinoic acid in human breast cancer cell line MCF-7 is dependent on HES-1 expression. Here we show that retinoic acid induces HES-1 expression via upregulation of transcription factor SOX9. By expressing a dominant negative form of SOX9, disrupting endogenous SOX9 activity, the retinoic acid-induced HES-1 mRNA expression was inhibited. We found an enhancer regulating HES-1 expression: two SOX9 binding sites upstream of the HES-1 gene that were capable of binding SOX9 in vitro. By performing chromatin immunoprecipitation, we showed that SOX9 binding to the HES-1 enhancer was induced by retinoic acid in vivo. In reporter assays, transfection of a SOX9 expression plasmid increased the activity of the HES-1 enhancer. The enhancer responded to retinoic acid; furthermore, the expression of a dominant negative SOX9 abolished this response. Taken together, we present here a novel transcriptional mechanism in regulating hormone-dependent cancer cell proliferation.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 141 57, Huddinge, Sweden. patrick.muller@ki.se
authors.forename: Patrick
authors.initials: P
authors.lastname: Müller
authors.forename: Justin D
authors.initials: JD
authors.lastname: Crofts
authors.forename: Ben S
authors.initials: BS
authors.lastname: Newman
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bridgewater
authors.forename: Chin-Yo
authors.initials: CY
authors.lastname: Lin
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: Anders
authors.initials: A
authors.lastname: Ström