Histone deacetylase 10 promotes autophagy-mediated cell survival

Significance Resistance to chemotherapy is one of the major challenges in oncology. Neuroblastoma is the most common extracranial solid tumor in childhood, and the successful response of high-risk patients to chemotherapy remains poor. Our work showed that the so far poorly studied histone deacetylase (HDAC)10 promotes autophagy-mediated cell survival and signals poor outcome in independent high-risk patient cohorts. Inhibition of HDAC10 sensitized tumor cells for cytotoxic drug treatment. These results offer HDAC10 as a potential biomarker for treatment response of high-risk tumors and open new avenues for developing selective treatment strategies to bypass drug resistance of these tumors. 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.

[1]  R. Stallings,et al.  LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression , 2012, Nature Genetics.

[2]  D. Gisselsson,et al.  Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis , 2012, Genes, chromosomes & cancer.

[3]  Axel Benner,et al.  FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  M. Murphy,et al.  HSP70 Inhibition by the Small-Molecule 2-Phenylethynesulfonamide Impairs Protein Clearance Pathways in Tumor Cells , 2011, Molecular Cancer Research.

[5]  R. Eils,et al.  Concurrent detection of autolysosome formation and lysosomal degradation by flow cytometry in a high-content screen for inducers of autophagy , 2011, BMC Biology.

[6]  D. Lev,et al.  Autophagy blockade enhances HDAC inhibitors’ pro-apoptotic effects , 2011, Autophagy.

[7]  P. Grandi,et al.  Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes , 2011, Nature Biotechnology.

[8]  E. Biçaku,et al.  Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy , 2011, Breast Cancer Research and Treatment.

[9]  Xiequn Chen,et al.  Targeting Autophagy Augments In Vitro and In Vivo Antimyeloma Activity of DNA-Damaging Chemotherapy , 2011, Clinical Cancer Research.

[10]  N. Chen,et al.  Autophagy as a therapeutic target in cancer , 2011, Cancer biology & therapy.

[11]  Ming-Shiang Wu,et al.  Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma , 2010, Autophagy.

[12]  Ju-Hee Lee,et al.  Inhibition of histone deacetylase 10 induces thioredoxin-interacting protein and causes accumulation of reactive oxygen species in SNU-620 human gastric cancer cells , 2010, Molecules and cells.

[13]  P. Northcott,et al.  HDAC5 and HDAC9 in Medulloblastoma: Novel Markers for Risk Stratification and Role in Tumor Cell Growth , 2010, Clinical Cancer Research.

[14]  J. Taylor,et al.  HDAC6 controls autophagosome maturation essential for ubiquitin‐selective quality‐control autophagy , 2010, The EMBO journal.

[15]  N. Mizushima,et al.  Methods in Mammalian Autophagy Research , 2010, Cell.

[16]  A. Zylicz,et al.  Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology , 2010, Nature.

[17]  Peng Huang,et al.  Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation , 2009, Journal of cellular and molecular medicine.

[18]  F. Westermann,et al.  MYCN/MYC-mediated drug resistance mechanisms in neuroblastoma. , 2010, International journal of clinical pharmacology and therapeutics.

[19]  Ya-Li Yao,et al.  Histone Deacetylase 10 Relieves Repression on the Melanogenic Program by Maintaining the Deacetylation Status of Repressors* , 2009, The Journal of Biological Chemistry.

[20]  O. Witt,et al.  Targeting of HDAC8 and investigational inhibitors in neuroblastoma , 2009, Expert opinion on investigational drugs.

[21]  Amanda K. Frank,et al.  A small molecule inhibitor of inducible heat shock protein 70. , 2009, Molecular cell.

[22]  J. Cox,et al.  Proteomics strategy for quantitative protein interaction profiling in cell extracts , 2009, Nature Methods.

[23]  M. Mann,et al.  Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions , 2009, Science.

[24]  O. Witt,et al.  HDAC family: What are the cancer relevant targets? , 2009, Cancer letters.

[25]  O. Witt,et al.  Targeting histone deacetylases in neuroblastoma. , 2009, Current pharmaceutical design.

[26]  Barbara Hero,et al.  Histone Deacetylase 8 in Neuroblastoma Tumorigenesis , 2009, Clinical Cancer Research.

[27]  Qing-Rong Chen,et al.  An integrated cross-platform prognosis study on neuroblastoma patients. , 2008, Genomics.

[28]  A. Cuervo,et al.  The Chaperone-Mediated Autophagy Receptor Organizes in Dynamic Protein Complexes at the Lysosomal Membrane , 2008, Molecular and Cellular Biology.

[29]  Y. Iwamoto,et al.  Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. , 2008, Anticancer research.

[30]  K. Sakamoto,et al.  Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation. , 2008, Cancer research.

[31]  Z. Elazar,et al.  Utilizing flow cytometry to monitor autophagy in living mammalian cells , 2008, Autophagy.

[32]  M. McNutt,et al.  Autophagy induced by suberoylanilide hydroxamic acid in Hela S3 cells involves inhibition of protein kinase B and up-regulation of Beclin 1. , 2008, The international journal of biochemistry & cell biology.

[33]  J. Taylor,et al.  HDAC6 at the Intersection of Autophagy, the Ubiquitin-proteasome System, and Neurodegeneration , 2007, Autophagy.

[34]  K. Glaser.  HDAC inhibitors: clinical update and mechanism-based potential. , 2007, Biochemical pharmacology.

[35]  M. Jäättelä,et al.  The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions , 2007, FEBS letters.

[36]  J. Cleveland,et al.  Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. , 2007, Blood.

[37]  J. Dice.  Chaperone-Mediated Autophagy , 2007, Autophagy.

[38]  Dimitra Keramisanou,et al.  Involvement of heat shock protein-70 in the mechanism of hydrogen peroxide-induced DNA damage: the role of lysosomes and iron. , 2007, Free radical biology & medicine.

[39]  Per O. Seglen,et al.  Methods for Monitoring Autophagy from Yeast to Human , 2007, Autophagy.

[40]  Jessica E. Bolden,et al.  Anticancer activities of histone deacetylase inhibitors , 2006, Nature Reviews Drug Discovery.

[41]  I. Oehme,et al.  Agonists of an ecdysone-inducible mammalian expression system inhibit Fas Ligand- and TRAIL-induced apoptosis in the human colon carcinoma cell line RKO , 2006, Cell Death and Differentiation.

[42]  R. Kopito,et al.  HDAC6 and Microtubules Are Required for Autophagic Degradation of Aggregated Huntingtin* , 2005, Journal of Biological Chemistry.

[43]  Terje Johansen,et al.  p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death , 2005, The Journal of cell biology.

[44]  F. Berthold,et al.  Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. , 2005, The Lancet. Oncology.

[45]  James Bradner,et al.  Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90 , 2005, Journal of Biological Chemistry.

[46]  P. Marks,et al.  Apoptotic and autophagic cell death induced by histone deacetylase inhibitors , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J. Nylandsted,et al.  Heat Shock Protein 70 Promotes Cell Survival by Inhibiting Lysosomal Membrane Permeabilization , 2004, The Journal of experimental medicine.

[48]  J. Vance,et al.  The Deacetylase HDAC6 Regulates Aggresome Formation and Cell Viability in Response to Misfolded Protein Stress , 2003, Cell.

[49]  Stuart L Schreiber,et al.  Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. V. van Kuilenburg,et al.  Histone deacetylases (HDACs): characterization of the classical HDAC family. , 2003, The Biochemical journal.

[51]  G. Brodeur.  Neuroblastoma: biological insights into a clinical enigma , 2003, Nature Reviews Cancer.

[52]  Xose S. Puente,et al.  Human Autophagins, a Family of Cysteine Proteinases Potentially Implicated in Cell Degradation by Autophagy* , 2003, The Journal of Biological Chemistry.

[53]  Fred Asselbergs,et al.  Cloning and Functional Characterization of HDAC11, a Novel Member of the Human Histone Deacetylase Family* , 2002, The Journal of Biological Chemistry.

[54]  Xiao-Fan Wang,et al.  HDAC6 is a microtubule-associated deacetylase , 2002, Nature.

[55]  T. Yao,et al.  Molecular Cloning and Characterization of a Novel Histone Deacetylase HDAC10* , 2002, The Journal of Biological Chemistry.

[56]  J. Dice,et al.  A molecular chaperone complex at the lysosomal membrane is required for protein translocation. , 2001, Journal of cell science.

[57]  S. Emr,et al.  Autophagy as a regulated pathway of cellular degradation. , 2000, Science.

[58]  Wei Gu,et al.  Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain , 1997, Cell.

[59]  T. Takano,et al.  Acridine orange as a fluorescent probe for lysosomal proton pump. , 1982, Journal of biochemistry.