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

• Published in: Cell death & disease Vol. 6; no. 2; p. e1657
• Main Authors: 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, Oehme, I
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-02-2015; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/109; 13/2; 13/31; 13/51; 13/89; 13/95; 64/60; 692/699/67/1059/602; 692/699/67/1922; 692/699/67/2332; 82/51; 82/80; 96/31; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Blotting, Western; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Survival - drug effects; Female; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids; Immunology; Indoles - pharmacology; Life Sciences; Mice; Mice, Nude; Neuroblastoma - metabolism; Original; original-article; Repressor Proteins - genetics; Repressor Proteins - metabolism; Tretinoin - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.24

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.