Broad-spectrum HDAC inhibitors promote autophagy through FOXO transcription factors in neuroblastoma
Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spec...
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| Hauptverfasser: | , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
24 April 2021
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| In: |
Cells
Year: 2021, Jahrgang: 10, Heft: 5, Pages: 1-18 |
| ISSN: | 2073-4409 |
| DOI: | 10.3390/cells10051001 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cells10051001 Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2073-4409/10/5/1001 
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| Verfasserangaben: | Katharina Körholz, Johannes Ridinger, Damir Krunic, Sara Najafi, Xenia F. Gerloff, Karen Frese, Benjamin Meder, Heike Peterziel, Silvia Vega-Rubin-de-Celis, Olaf Witt and Ina Oehme |
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| 245 | 1 | 0 | |a Broad-spectrum HDAC inhibitors promote autophagy through FOXO transcription factors in neuroblastoma |c Katharina Körholz, Johannes Ridinger, Damir Krunic, Sara Najafi, Xenia F. Gerloff, Karen Frese, Benjamin Meder, Heike Peterziel, Silvia Vega-Rubin-de-Celis, Olaf Witt and Ina Oehme |
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| 520 | |a Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spectrum HDAC inhibitors (HDACi) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity (Transcription factor EB—TFEB, forkhead boxO—FOXO) and autophagic flux in neuroblastoma cells. In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma. | ||
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