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Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):E2592-601. doi: 10.1073/pnas.1300113110. Epub 2013 Jun 25.

Histone deacetylase 10 promotes autophagy-mediated cell survival.

Author information

1
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.

KEYWORDS:

HDAC inhibitor; childhood tumors; drug resistance

PMID:
23801752
PMCID:
PMC3710791
DOI:
10.1073/pnas.1300113110
[Indexed for MEDLINE]
Free PMC Article

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