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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. and Linke, J.P. and Böck, B.C. and Milde, T. and Lodrini, M. and Hartenstein, B. and Wiegand, I. and Eckert, C. and Roth, W. and Kool, M. and Kaden, S. and Gröne, H.J. and Schulte, J.H. and Lindner, S. and Hamacher-Brady, A. and Brady, N.R. and 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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