PUBLICATION
Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma
- Authors
- Körholz, K., Ridinger, J., Krunic, D., Najafi, S., Gerloff, X.F., Frese, K., Meder, B., Peterziel, H., Vega-Rubin-de-Celis, S., Witt, O., Oehme, I.
- ID
- ZDB-PUB-210501-29
- Date
- 2021
- Source
- Cells 10(5): (Journal)
- Registered Authors
- Frese, Karen, Meder, Benjamin
- Keywords
- FOXO1, FOXO3a, macroautophagy, neuroblastoma, panobinostat, vorinostat
- MeSH Terms
-
- Animals
- Antimalarials/pharmacology
- Autophagy*
- Chloroquine/pharmacology
- Forkhead Box Protein O1/genetics
- Forkhead Box Protein O1/metabolism*
- Forkhead Box Protein O3/genetics
- Forkhead Box Protein O3/metabolism*
- Gene Expression Regulation, Neoplastic/drug effects*
- Histone Deacetylase Inhibitors/pharmacology*
- Humans
- Mechanistic Target of Rapamycin Complex 1/genetics
- Mechanistic Target of Rapamycin Complex 1/metabolism
- Neuroblastoma/drug therapy
- Neuroblastoma/metabolism
- Neuroblastoma/pathology*
- Tumor Cells, Cultured
- Vorinostat/pharmacology
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 33923163 Full text @ Cells
Citation
Körholz, K., Ridinger, J., Krunic, D., Najafi, S., Gerloff, X.F., Frese, K., Meder, B., Peterziel, H., Vega-Rubin-de-Celis, S., Witt, O., Oehme, I. (2021) Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma. Cells. 10(5).
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping