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



Kershaw, Stephen, Morgan, David J, Boyd, James ORCID: 0000-0003-0858-7179, Spiller, David G, Kitchen, Gareth, Zindy, Egor, Iqbal, Mudassar, Rattray, Magnus, Sanderson, Chris M ORCID: 0000-0002-7301-3537, Brass, Andrew
et al (show 4 more authors) (2020) Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional HDAC6 pathway. Journal of Cell Science, 133 (11). jcs242842-.

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Abstract

Glucocorticoids (GCs) act through the glucocorticoid receptor (GR, also known as NR3C1) to regulate immunity, energy metabolism and tissue repair. Upon ligand binding, activated GR mediates cellular effects by regulating gene expression, but some GR effects can occur rapidly without new transcription. Here, we show that GCs rapidly inhibit cell migration, in response to both GR agonist and antagonist ligand binding. The inhibitory effect on migration is prevented by GR knockdown with siRNA, confirming GR specificity, but not by actinomycin D treatment, suggesting a non-transcriptional mechanism. We identified a rapid onset increase in microtubule polymerisation following GC treatment, identifying cytoskeletal stabilisation as the likely mechanism of action. HDAC6 overexpression, but not knockdown of αTAT1, rescued the GC effect, implicating HDAC6 as the GR effector. Consistent with this hypothesis, ligand-dependent cytoplasmic interaction between GR and HDAC6 was demonstrated by quantitative imaging. Taken together, we propose that activated GR inhibits HDAC6 function, and thereby increases the stability of the microtubule network to reduce cell motility. We therefore report a novel, non-transcriptional mechanism whereby GCs impair cell motility through inhibition of HDAC6 and rapid reorganization of the cell architecture.

Item Type: Article
Uncontrolled Keywords: HDAC6, Cell migration, Glucocorticoid, Microtubule, Quantitative imaging
Depositing User: Symplectic Admin
Date Deposited: 05 Jun 2020 07:57
Last Modified: 18 Jan 2023 23:50
DOI: 10.1242/jcs.242842
Open Access URL: https://jcs.biologists.org/content/133/11/jcs24284...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3089498