Neuroblastoma cells depend on HDAC11 for mitotic cell cycle progression and survival
| Autor: | Theresa M Thole, Thomas Hielscher, Hedwig E. Deubzer, Sebastian Pfeil, Olaf Witt, Matthias Fischer, Angelika Eggert, Marco Lodrini, Johannes Fabian, Ulrike Heinicke, Annette Kopp-Schneider, Jasmin Wuenschel, Simone Fulda |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Cell division Cell Survival Immunology Cell Gene Expression Mitosis Apoptosis Biology Disease-Free Survival Histone Deacetylases 03 medical and health sciences Cellular and Molecular Neuroscience Neuroblastoma 0302 clinical medicine Mitotic cell cycle Cell Line Tumor medicine Humans CENPA Cell Cycle Cell Biology medicine.disease Genes cdc 030104 developmental biology medicine.anatomical_structure Tumor progression 030220 oncology & carcinogenesis Cancer research Original Article Neoplasm Recurrence Local Function and Dysfunction of the Nervous System |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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