Histone deacetylase 10 promotes autophagy-mediated cell survival

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, Olaf Witt

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)E2592-E2601
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number28
DOIs
StatePublished - Jul 9 2013
Externally publishedYes

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Keywords

  • Childhood tumors
  • Drug resistance
  • Hdac inhibitor

ASJC Scopus subject areas

  • General

Cite this

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., & Witt, O. (2013). Histone deacetylase 10 promotes autophagy-mediated cell survival. Proceedings of the National Academy of Sciences of the United States of America, 110(28), E2592-E2601. https://doi.org/10.1073/pnas.1300113110