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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Böck, Barbara C. Roth, Wilfried Milde, Till Schulte, Johannes H. Hamacher-brady, Anne Linke, Jan-peter Kaden, Sylvia Wiegand, Inga Brady, Nathan R. Lindner, Sven Eckert, Christian Witt, Olaf Deubzer, Hedwig E. Kool, Marcel Lodrini, Marco Gröne, Hermann-josef Oehme, Ina Hartenstein, Bettina |
| Description | Author Affiliation: Oehme I ( Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany. i.oehme@dkfz.de); |
| Abstract | Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 28 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Autophagy Physiology Cell Survival Histone Deacetylases Cell Line, Tumor HSP70 Heat-Shock Proteins Metabolism Histone Deacetylase Inhibitors Pharmacology Neuroblastoma Enzymology Pathology Protein Binding Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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