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Histone deacetylase 10 promotes autophagy-mediated cell survival

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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...

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Main Authors: Oehme, Ina (Author) , Linke, Jan-Peter (Author) , Böck, Barbara (Author) , Milde, Till (Author) , Lodrini, Marco (Author) , Hartenstein, Bettina (Author) , Rettig, Inga Edeltraud (Author) , Eckert, Christian (Author) , Roth, Wilfried (Author) , Kool, Marcel (Author) , Kaden, Sylvia (Author) , Gröne, Hermann-Josef (Author) , Schulte, Johannes Hubertus (Author) , Lindner, Sven (Author) , Hamacher-Brady, Anne (Author) , Brady, Nathan (Author) , Deubzer, Hedwig (Author) , Witt, Olaf (Author)
Format: Article (Journal)
Language:English
Published: June 25, 2013
In: Proceedings of the National Academy of Sciences of the United States of America
Year: 2013, Volume: 110, Issue: 28, Pages: E2592-E2601
ISSN:1091-6490
DOI:10.1073/pnas.1300113110
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.1300113110
Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/110/28/E2592
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Author Notes:Ina Oehme, Jan-Peter Linke, Barbara C. Böck, Till Milde, Marco Lodrini, Bettina Hartenstein, Inga Wiegand, Christian Eckert, Wilfried Roth, Marcel Kool, Sylvia Kaden, Hermann-Josef Gröne, Johannes H. Schulte, Sven Lindner, Anne Hamacher-Brady, Nathan R. Brady, Hedwig E. Deubzer, and Olaf Witt
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Summary: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.
Item Description:Gesehen am 29.11.2021
Physical Description:Online Resource
ISSN:1091-6490
DOI:10.1073/pnas.1300113110

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