Journal Article

Histone deacetylase 10 promotes autophagy-mediated cell survival

Hermann-Josef Gröne, Ina Oehme, Olaf Witt, Sylvia Kaden, Marcel Kool, Jan-Peter Linke, Johannes H. Schulte, Nathan R. Brady, Bettina Hartenstein, Till Milde, Wilfried Roth, Inga Wiegand, Christian Eckert, Anne Hamacher-Brady, Hedwig E. Deubzer, Sven Lindner, Barbara C. Böck, Marco Lodrini

2013

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Autophagy / Autophagy - physiology / Biological Sciences / Cell Line, Tumor / Cell Survival - physiology / cell viability / cytotoxicity / DNA damage / doxorubicin / drug therapy / Gene expression / Heat shock proteins / heat-shock protein 70 / histone deacetylase / Histone Deacetylase Inhibitors - pharmacology / Histone Deacetylases - metabolism / Histone Deacetylases - physiology / HSP70 Heat-Shock Proteins - metabolism / Humans / isozymes / lysosomes / neoplasm cells / neoplasms / Neuroblastoma - enzymology / Neuroblastoma - pathology / oncogenes / patients / PNAS Plus / Protein Binding / Real-Time Polymerase Chain Reaction / Reverse Transcriptase Polymerase Chain Reaction / Stress response / Survival / Survival analysis / Tumors