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Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation

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Item Type:Article
Title:Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation
Creators Name:Rettig, I., Koeneke, E., Trippel, F., Mueller, W.C., Burhenne, J., Kopp-Schneider, A., Fabian, J., Schober, A., Fernekorn, U., von Deimling, A., Deubzer, H.E., Milde, T., Witt, O. and Oehme, I.
Abstract:For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential. Selective targeting of individual HDAC isozymes in defined tumor entities may therefore be an attractive alternative treatment approach. We have previously identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. Using small-molecule inhibitors, we now demonstrate that selective inhibition of HDAC8 exhibits antineuroblastoma activity without toxicity in two xenograft mouse models of MYCN oncogene-amplified neuroblastoma. In contrast, the unselective HDAC inhibitor vorinostat was more toxic in the same models. HDAC8-selective inhibition induced cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation was significantly enhanced, as demonstrated by elongated neurofilament-positive neurites and upregulation of NTRK1. Additionally, MYCN oncogene expression was downregulated in vitro and tumor cell growth was markedly reduced in vivo. Mechanistic studies suggest that cAMP-response element-binding protein (CREB) links HDAC8- and retinoic acid-mediated gene transcription. In conclusion, HDAC-selective targeting can be effective in tumors exhibiting HDAC isozyme-dependent tumor growth in vivo and can be combined with differentiation-inducing agents.
Keywords:Cell Survival, Histone Deacetylase Inhibitors, Histone Deacetylases, Hydroxamic Acids, Indoles, Neuroblastoma, Nude Mice, Repressor Proteins, Tretinoin, Tumor Cell Line, Western Blotting, Xenograft Model Antitumor Assays, Animals, Mice
Source:Cell Death & Disease
Publisher:Nature Publishing Group
Page Range:e1657
Date:19 February 2015
Official Publication:https://doi.org/10.1038/cddis.2015.24
PubMed:View item in PubMed

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