Faculty Collaboration Database

CREB-binding protein is a mediator of neuroblastoma cell death induced by the histone deacetylase inhibitor trichostatin A. Neoplasia 2007 Jun;9(6):495-503

Date

07/03/2007

Pubmed ID

17603632

Pubmed Central ID

PMC1899529

DOI

10.1593/neo.07262

Scopus ID

2-s2.0-34250822248 (requires institutional sign-in at Scopus site)   25 Citations

Abstract

The cytotoxic mechanism of the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) was explored in a neuroblastoma (NB) model. TSA induces cell death in neuroblastic-type NB cells by increasing the acetylation of Ku70, a Bax-binding protein. Ku70 acetylation causes Bax release and activation, triggering cell death. This response to TSA depends on the CREB-binding protein (CBP) acetylating Ku70. TSA-induced cell death response correlates with CBP expression. In stromaltype NB cell lines with low levels of CBP and relative resistance to TSA, increasing CBP expression disrupts Bax-Ku70 binding and sensitizes them to TSA. Reducing CBP expression in neuroblastic cell types causes resistance. Cytotoxic response to TSA is Bax-dependent. Interestingly, depleting NB cells of Ku70 also triggers Bax-dependent cell death, suggesting that conditions that leave Bax unbound to Ku70 result in cell death. We also show that CBP, Ku70, and Bax are expressed in human NB tumors and that CBP expression varies across cell types comprising these tumors, with the highest expression observed in neuroblastic elements. Together, these results demonstrate that CBP, Bax, and Ku70 contribute to a therapeutic response to TSA against NB and identify the possibility of using these proteins to predict clinical responsiveness to HDACI treatment.

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
Adrenal Glands
Antigens, Nuclear
Apoptosis
Blotting, Western
CREB-Binding Protein
Cell Proliferation
DNA-Binding Proteins
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids
Immunoprecipitation
Ku Autoantigen
Neuroblastoma
RNA, Small Interfering
Tumor Cells, Cultured
bcl-2-Associated X Protein