Published in:
01-04-2010 | Preclinical study
SOX9 mediates the retinoic acid-induced HES-1 gene expression in human breast cancer cells
Authors:
Patrick Müller, Justin D. Crofts, Ben S. Newman, Laura C. Bridgewater, Chin-Yo Lin, Jan-Åke Gustafsson, Anders Ström
Published in:
Breast Cancer Research and Treatment
|
Issue 2/2010
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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.