Endocrine Abstracts (2017) 50 OC4.2 | DOI: 10.1530/endoabs.50.OC4.2

Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional pathway involving HDAC6

Stephen Kershaw1, David Morgan1, James Boyd2, David Spiller1, Mudassar Iqbal1, Egor Zindy1, Andy Brass1, Laura Matthews3 & David Ray1


1University of Manchester, Manchester, UK; 2University of Liverpool, Liverpool, UK; 3University of Leeds, Leeds, UK.


Glucocorticoids (Gc) act through the glucocorticoid receptor (GR) to regulate immunity, energy metabolism, and tissue repair. The inactive GR is held in the cytoplasm in a multi-protein complex, which upon ligand binding undergoes a conformational change. Activated GR translocates to the nucleus to regulate gene expression (over hours), but some effects occur more rapidly. Gc inhibit cell migration through an uncertain mechanism. We now show a very rapid effect, and surprisingly find the GR agonist Dexamethasone, and antagonist, RU486, are equipotent. The migration effect was prevented by GR knockdown, confirming GR specificity, but not by actinomycin D treatment, suggesting a non-transcriptional mechanism. To investigate the Gc effect we analyzed microtubule network kinetics using plus end microtubule real time assays, which revealed Gc induction of tubulin acetylation – a marker of microtubule stability. Inhibition of the cytoplasmic deacetylase HDAC6, which deaceylates tubulin, mimicked the Gc effect, and HDAC6 overexpression rescued the Gc effect, implicating HDAC6 as a Gc effector. We found interaction between GR and HDAC6, using fluorescent cross correlation spectroscopy, and showed HDAC6 nuclear translocation following Gc treatment. We propose that Gc treatment displaces HDAC6 from cytoplasmic microtubules and therefore restricts interaction with it substrate, driving increased tubulin acetylation, increasing stability of the microtubule network and reducing cell motility. We propose that Gc treatment displaces HDAC6 from cytoplasmic microtubules and therefore restricts interaction with it substrate, driving increased tubulin acetylation, increasing stability of the microtubule network and reducing cell motility. We therefore discover a novel, non-transcriptional mechanism whereby GR agonists and antagonists, through actions on HDAC6, rapidly reorganize cell architecture to change cell function.

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