Neuroblastoma cells depend on HDAC11 for mitotic cell cycle progression and survival
Open accessAbstract
The number of long-term survivors of high-risk neuroblastoma remains discouraging, with 10-year survival as low as 20%, despite decades of considerable international efforts to improve outcome. Major obstacles remain and include managing resistance to induction therapy, which causes tumor progression and early death in high-risk patients, and managing chemotherapy-resistant relapses, which can occur years after the initial diagnosis. Identifying and validating novel therapeutic targets is essential to improve treatment. Delineating and deciphering specific functions of single histone deacetylases in neuroblastoma may support development of targeted acetylome-modifying therapeutics for patients with molecularly defined high-risk neuroblastoma profiles. We show here that HDAC11 depletion in MYCN-driven neuroblastoma cell lines strongly induces cell death, mostly mediated by apoptotic programs. Genes necessary for mitotic cell cycle progression and cell division were most prominently enriched in at least two of three time points in whole-genome expression data combined from two cell systems, and all nine genes in these functional categories were strongly repressed, including CENPA, KIF14, KIF23 and RACGAP1. Enforced expression of one selected candidate, RACGAP1, partially rescued the induction of apoptosis caused by HDAC11 depletion. High-level expression of all nine genes in primary neuroblastomas significantly correlated with unfavorable overall and event-free survival in patients, suggesting a role in mediating the more aggressive biological and clinical phenotype of these tumors. Our study identified a group of cell cycle-promoting genes regulated by HDAC11, being both predictors of unfavorable patient outcome and essential for tumor cell viability. The data indicate a significant role of HDAC11 for mitotic cell cycle progression and survival of MYCN-amplified neuroblastoma cells, and suggests that HDAC11 could be a valuable drug target.
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This evidence is more relevant in neuroblastoma cells characterized by MYCN amplification.
“This evidence is more relevant in neuroblastoma cells characterized by MYCN amplification (Thole et al., 2017).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Thole et al., 2017
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References 83 · Cited by 67
- Authors
- Thole, T. M., Lodrini, M., Fabian, J., Wuenschel, J., Pfeil, S., Hielscher, T., Kopp-Schneider, A., Heinicke, U., Fulda, S., Witt, O., Eggert, A., Fischer, M., & Deubzer, H. E.
- Affiliations
- German Cancer Research Center (DE)
- Charité – Universitätsmedizin Berlin (DE)
- University Hospital Frankfurt (DE)
- University of Cologne (DE)
- Corresponding author
- Deubzer, Hedwig E
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2017-03-02
- Volume
- 8
- Issue
- 3
- Pages
- e2635-e2635
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5386552
- OpenAlex
- W2593135290
- Cited by
- 67
- References
- 83
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 10 · 2023: 8 · 2022: 9 · 2021: 8 · 2020: 9 · 2019: 9 · 2018: 3 · 2017: 4
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- Bundesministerium für Bildung und Forschung
- Deutsche Krebshilfe
- Berlin Institute of Health
- Topics
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Keywords
- neuroblastoma, HDAC11, histone deacetylase, MYCN amplification, apoptosis, RACGAP1, CENP-A, KIF14, KIF23, cell survival, prognostic factors, therapeutic target, acetylome
- MeSH terms
- Cell Cycle, Cell Survival, Histone Deacetylases, Humans, Mitosis, Neoplasm Recurrence, Local, Neuroblastoma, Gene Expression, Apoptosis, Disease-Free Survival, Genes, cdc, Cell Line, Tumor
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