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Histone deacetylase 10 promotes autophagy-mediated cell survival

Item Type:Article
Title:Histone deacetylase 10 promotes autophagy-mediated cell survival
Creators Name:Oehme, I., Linke, J.P., Böck, B.C., Milde, T., Lodrini, M., Hartenstein, B., Wiegand, I., Eckert, C., Roth, W., Kool, M., Kaden, S., Gröne, H.J., Schulte, J.H., Lindner, S., Hamacher-Brady, A., Brady, N.R., Deubzer, H.E. and Witt, O.
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.
Keywords:Drug Resistance, HDAC Inhibitor, Childhood Tumors
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:E2592-E2601
Date:9 July 2013
Official Publication:https://doi.org/10.1073/pnas.1300113110
PubMed:View item in PubMed

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