Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 13, Pages 4842-4847Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0408351102
Keywords
cAMP-response element-binding protein; histone acetyltransferase
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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 HDACl 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.
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