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HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma. Neoplasia 2011 Aug;13(8):726-34

Date

08/19/2011

Pubmed ID

21847364

Pubmed Central ID

PMC3156663

DOI

10.1593/neo.11558

Scopus ID

2-s2.0-80051496447   76 Citations

Abstract

Ku70 was first characterized as a nuclear factor that binds DNA double-strand breaks in nonhomolog end-joining DNA repair. However, recent studies have shown that Ku70 is also found in the cytoplasm and binds Bax, preventing Bax-induced cell death. We have shown that, in neuroblastoma cells, the binding between Ku70 and Bax depends on the acetylation status of Ku70, such that, when Ku70 is acetylated, Bax is released from Ku70, triggering cell death. Thus, to survive, in neuroblastoma cells, cytoplasmic Ku70 acetylation status is carefully regulated such that Ku70 is maintained in a deacetylated state, keeping Bax complexed with Ku70. We have shown that overexpression of CREB-binding protein (CBP), a known acetyltransferase that acetylates Ku70, releases Bax from Ku70, triggering apoptosis. Although we have shown that blocking deacetylase activity using non-type-specific inhibitors also triggers Ku70 acetylation and Bax-dependent cell death, the targets of these deacetylase inhibitors in neuroblastoma cells remain unknown. Here, we demonstrate that, in neuroblastoma cells, histone deacetylase 6 (HDAC6) binds Ku70 and Bax in the cytoplasm and that knocking down HDAC6 or using an HDAC6-specific inhibitor triggers Bax-dependent cell death. Our results show that HDAC6 regulates the interaction between Ku70 and Bax in neuroblastoma cells and may be a therapeutic target in this pediatric solid tumor.

Author List

Subramanian C, Jarzembowski JA, Opipari AW Jr, Castle VP, Kwok RP

Author

Jason A. Jarzembowski MD, PhD Sr Associate Dean, CEO CSG, Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylation
Antigens, Nuclear
CREB-Binding Protein
Cell Death
Cell Line, Tumor
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Gene Silencing
Histone Deacetylase 6
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Ku Autoantigen
Neuroblastoma
Protein Binding
bcl-2-Associated X Protein