Histone deacetylase inhibition leads to Reduced neural crest cell migration

The formation of neural crest cells (NCCs) takes place after neurulation in the developing embryo. Prior to migration, NCCs undergo epithelial to mesenchymal transition (EMT), characterized by extensively altered cellular morphology by the suppression of E-cadherin transcription (Bhatt et al., 2013). This transcriptional regulation, resulting in released cell adhesion is affected by transcription factors of the Snail family (Cano et al., 2000; Taneyhill et al., 2007; Bolos et al., 2016). The effect of HDAC inhibition on EMT has been studied most extensively in the context of cancer treatment, and numerous studies have been devoted to explore the effectiveness of chemical HDAC inhibitors as potential chemotherapeutics (Drummond et al., 2005). Several studies have found that HDAC inhibition attenuates EMT, though comparatively few focusing on EMT in pre-migratory NCCs. However chromatin immunoprecipitation experiments have demonstrated that a genetic loci of importance to EMT, a target of a Snail family transcription factor, in pre-migratory NCCs exhibits dramatic deacetylation at the time of EMT initiation (Strobl-Mazzulla and Bronner, 2012). This indicates that HDAC inhibition is likely to affect the process of EMT in NCCs as well. Furthermore, in vitro studies have shown attenuation of NCC migration in response to chemical HDAC inhibition (Dreser et al., 2015; Pallocca et al., 2016) and NCC migration has been shown to be affected in vivo by antisense mediated genetic knock down of a specific HDAC encoding gene (DeLaurier et al., 2012).

In vitro scratch assay data has shown reducing effects of HDAC inhibitors on the migration of NCCs. Different HDAC inhibitors have been shown to exert similar gene regulatory effects on NCCs in vitro (Dreser et al., 2015; Pallocca et al., 2016). Genetic manipulations have been applied in vivo to show that HDAC4 is important to cranial NCC migration in developing zebrafish (DeLaurier et al., 2012).

In an in vivo situation, it is uncertain whether observed reduction of NCC migration is caused by the effects of HDAC vs. HAT action on histones, or other proteins that exhibit altered acetylation patterns in response to HDAC inhibition, e.g. tubulin (Hubbert et al., 2002). Members of the Snail family of proteins have been reported to be dispensable in mammals (Murray and Gridley, 2006), indicating that conclusions regarding the importance of HDAC activity in relation to Snail regulation and EMT must be made with caution.