Histone deacetylase 10 promotes autophagy-mediated cell survival

Abstract

Tumor cells activate autophagy in response to chemotherapyinduced 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.drug resistance | HDAC inhibitor | childhood tumors A utophagy is an evolutionarily highly conserved process that can be induced by metabolic or therapeutic stress, such as DNA damage-inducing drugs (1). The two dominant types of autophagy are macroautophagy and chaperone-mediated autophagy (CMA) (2). Macroautophagy is regulated by autophagyrelated genes (ATGs), including beclin-1 (ATG6) and microtubule-associated protein 1 light chain 3 (LC3) (ATG8), and involves the sequestration of cytoplasmic components within a double-membrane structure called the autophagosome and successive delivery to lysosomes for degradation (reviewed in ref.3). CMA targets specific cytosolic proteins to the lysosomes for protein degradation (4). During CMA, the cytosolic chaperone heat shock cognate (Hsc)70 binds proteins targeted for degradation and translocates them to the lysosomes (5), where they bind to the substrate protein receptor lysosome-associated membrane protein type 2A (LAMP-2A) (6).Inhibition of histone deacetylases (HDACs) by HDAC inhibitors (HDACis) have been shown to cause significant anti-tumor effects, including cell-cycle arrest, differentiation, and apoptosis, in a broad spectrum of hematologic and solid tumors (reviewed in ref. 7). The efficacy of HDACis are currently being evaluated for treating various cancers in clinical trials (7-9). Recent research carried out in several tumor cell lines has shown that apoptosis induced by HDACis i...

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

“…These data suggest that HDAC10 does not compensate for low HDAC6 expression in a similar fashion as reported for the class I enzymes HDAC1 and HDAC2. 48,49 Although a number of HDAC6-specific inhibitors have been developed for research purposes, no such compound has yet become approved for clinical applications. Among the three HDAC6-specific inhibitors Tubacin, Tubastatin A, and ST-80, Tubacin appeared to be most potent exerting effects on tubulin acetylation in urothelial carcinoma cells starting already from a dose of 2.5 μM.…”

Histone Deacetylase 10 Regulates the Cell Cycle G2/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway

“…HDAC10, together with HDAC1 and -3, and SIRT1 and -2, regulated the 3=-end processing machinery by modulating deacetylation of CFIm25 and PAP, ultimately affecting the CFIm25-PAP interaction and PAP localization (27). In neuroblastoma cells, HDAC10 promoted autophagy-mediated survival and protected cells from cytotoxic agents by direct interaction with, and deacetylation of, Hsc70/ Hsp70 (28).…”

“…In contrast, for neuroblastomas, medulloblastomas, and chronic lymphocytic leukemias, HDAC10 expression was significantly increased in tumor tissues and correlated with poor survival (28,32). Although HDAC10 is ubiquitously expressed (21,23,24), its role in cell cycle regulation is largely unknown.…”

Effect of Nutrition on Statural Growth

“…HDAC6 has been defined as a basal component of the autophagic machinery [176], and HDAC10 has recently been shown to promote autophagy-mediated survival of neuroblastoma cells [177] and to activate autophagy in liver cells [57]. Knockdown of HDAC10 disrupts autophagy and induces accumulation of autophagosomes as well as P62/sequestosome1 protein level in neuroblastoma cells [177]. …”