Hyaluronate synthase-2 overexpression alters estrogen dependence and induces histone deacetylase inhibitor-like effects on ER-driven genes in MCF7 breast tumor cells

• Published in: Molecular and cellular endocrinology 2017-03, Vol.444, p.48-58
• Main Authors: Vanneste, Marion, Hanoux, Vincent, Bouakka, Mohammed, Bonnamy, Pierre-Jacques
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Biochemistry, Molecular Biology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Behavior; Cellular Biology; E1A-Associated p300 Protein - metabolism; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen signaling; Estrogens - pharmacology; Female; Gene Expression Regulation, Neoplastic - drug effects; Genes, Reporter; Glucuronosyltransferase - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone deacetylases; Humans; Hyaluronan; Hyaluronan Receptors - metabolism; Hyaluronan Synthases; Hyaluronate synthase 2; Hyaluronic Acid - metabolism; Hydroxamic Acids - pharmacology; Life Sciences; MCF-7 Cells; Methylation - drug effects; Molecular biology; Phosphorylation - drug effects; Phosphoserine - metabolism; Protein Binding - drug effects; Subcellular Fractions - metabolism
• ISSN: 0303-7207; 1872-8057; 0303-7207
• DOI: 10.1016/j.mce.2017.01.046

In breast carcinoma cells, high levels of hyaluronan (HA) and its CD44 receptor are frequently associated with alteration in estrogen signaling. We demonstrate that stable hyaluronate synthase 2 (HAS2) overexpression in estrogen receptor α (ERα) -positive MCF7 cells oppositely altered estrogen dependence of cell growth and its sensitivity towards antiestrogens. Albeit without effect on ERα expression and estradiol binding properties, HAS2 overexpression increased ERα Ser118 phosphorylation as well as transcriptional activity of estrogen in an ERE-luciferase reporter gene assay. However, HAS2 overexpression induced partial silencing of E2 driven-genes without affecting the magnitude of regulation by estradiol. This effect was associated with half-reduction in the activity of nuclear histone deacetylases (HDACs) through a post-translational mechanism likely consecutive to the enhanced expression of the histone acetyl-transferase EP300. In conclusion, increase in HA/CD44 interactions may contribute, through an HDAC inhibitor-like and ER-independent mechanism, to the silencing of estrogen–driven genes in breast carcinoma. [Display omitted] •HAS2 overexpression promotes partial escape to estrogen dependency.•HDAC inhibitor-like effects are observed upon estrogen-driven genes expression.•These effects are associated with decline in class I histone deacetylases activity.•An EP300-mediated inhibition of nuclear histone deactylase activity is suggested.•A regulatory role of HDACs on transcriptional co-repressors activity is proposed.