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| Home > Publications database > Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. > print |
| Home > Publications database > Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. > print |
| 001 | 127368 | ||
| 005 | 20240228140922.0 | ||
| 024 | 7 | _ | |a 10.1038/cddis.2015.24 |2 doi |
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| 037 | _ | _ | |a DKFZ-2017-03393 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |a Rettig, I. |0 P:(DE-HGF)0 |b 0 |e First author |
| 245 | _ | _ | |a Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. |
| 260 | _ | _ | |a London [u.a.] |c 2015 |b Nature Publishing Group |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1524127769_11666 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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. |
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| 650 | _ | 7 | |a Histone Deacetylase Inhibitors |2 NLM Chemicals |
| 650 | _ | 7 | |a Hydroxamic Acids |2 NLM Chemicals |
| 650 | _ | 7 | |a Indoles |2 NLM Chemicals |
| 650 | _ | 7 | |a PCI 34051 |2 NLM Chemicals |
| 650 | _ | 7 | |a Repressor Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Tretinoin |0 5688UTC01R |2 NLM Chemicals |
| 650 | _ | 7 | |a HDAC8 protein, human |0 EC 3.5.1.98 |2 NLM Chemicals |
| 650 | _ | 7 | |a HDAC8 protein, mouse |0 EC 3.5.1.98 |2 NLM Chemicals |
| 650 | _ | 7 | |a Histone Deacetylases |0 EC 3.5.1.98 |2 NLM Chemicals |
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| 700 | 1 | _ | |a Trippel, F. |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Mueller, W. C. |b 3 |
| 700 | 1 | _ | |a Burhenne, J. |b 4 |
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| 700 | 1 | _ | |a Fabian, J. |0 P:(DE-HGF)0 |b 6 |
| 700 | 1 | _ | |a Schober, A. |b 7 |
| 700 | 1 | _ | |a Fernekorn, U. |b 8 |
| 700 | 1 | _ | |a von Deimling, A. |0 P:(DE-He78)a8a10626a848d31e70cfd96a133cc144 |b 9 |u dkfz |
| 700 | 1 | _ | |a Deubzer, H. E. |0 P:(DE-HGF)0 |b 10 |
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| 700 | 1 | _ | |a Witt, O. |0 P:(DE-He78)143af26de9d57bf624771616318aaf7c |b 12 |u dkfz |
| 700 | 1 | _ | |a Oehme, Ina |0 P:(DE-He78)908367a659dea9e28dac34592b3c46e5 |b 13 |e Last author |u dkfz |
| 773 | _ | _ | |a 10.1038/cddis.2015.24 |g Vol. 6, no. 2, p. e1657 - |0 PERI:(DE-600)2541626-1 |n 2 |p e1657 - |t Cell death & disease |v 6 |y 2015 |x 2041-4889 |
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