Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors.
Histone deacetylase inhibitors (HDACIs) are therapeutic drugs that inhibit deacetylase activity, thereby increasing acetylation of many proteins, including histones. HDACIs have antineoplastic effects in preclinical and clinical trials and are being considered for cancers with unmet therapeutic need, including neuroblastoma (NB). Uncertainty of how HDACI-induced protein acetylation leads to cell death, however, makes it difficult to determine which tumors are likely to be responsive to these agents. Here, we show that NB cells are sensitive to HDACIs, and that the mechanism by which HDACIs induce apoptosis involves Bax. In these cells, Bax associates with cytoplasmic Ku70, a protein that typically increases chemotherapy resistance. Our data show that in NB cells Ku70 binds to Bax in an acetylation-sensitive manner. Upon HDACI treatment, acetylated Ku70 releases Bax, allowing it to translocate to mitochondria and trigger cytochrome c release, leading to caspase-dependent death. This study shows that Ku70 is an important Bax-binding protein, and that this interaction can be therapeutically regulated in NB cells. Whereas the Bax-binding ability of Ku70 allows it to block apoptosis in response to certain agents, it is also a molecular target for the action of HDACIs, and in this context, a mediator of NB cell death.
Subramanian
Chitra
C
Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Opipari
Anthony W
AW
Bian
Xin
X
Castle
Valerie P
VP
Kwok
Roland P S
RP
D000107:Acetylation; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002087:Butyrates / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D047468:Immunoprecipitation; D000072200:Ku Autoantigen; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D034961:Antigens, Nuclear; C494827:Bax protein, mouse; D002087:Butyrates; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins; C012589:trichostatin A; D045304:Cytochromes c; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen