SOX9 mediates the retinoic acid-induced HES-1 gene expression in human breast cancer cells

Patrick Müller (1) , Justin D. Crofts (2) , Ben S. Newman (2) , Laura C. Bridgewater (2) , Chin-Yo Lin (2) , Jan-Åke Gustafsson (1, 3) , Anders Ström (3)

1 Department of Biosciences and Nutrition
2 Department of Microbiology and Molecular Biology
3 Center for Nuclear Receptors and Cell Signaling, Department of Cell Biology and Biochemistry

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.

Mots clés: atRA; HES-1; SOX9; Proliferation

Patrick Müller, Justin D. Crofts, Ben S. Newman, Laura C. Bridgewater, Chin-Yo Lin, et al.. SOX9 mediates the retinoic acid-induced HES-1 gene expression in human breast cancer cells. Breast Cancer Research and Treatment, 2009, 120 (2), pp.317-326. ⟨10.1007/s10549-009-0381-6⟩. ⟨hal-00535353⟩