Document Detail

Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma.
MedLine Citation:
PMID:  22214764     Owner:  NLM     Status:  MEDLINE    
ZBP-89, a zinc finger transcription factor, participates in histone deacetylases inhibitors (HDACi)-mediated growth arrest and apoptosis in cancer cells. p53 mutants may interact with ZBP-89 that transcriptionally regulates p21(Waf1) (p21). However, this interaction and its consequence in cancer treatments are poorly understood. In this study, we demonstrate that ZBP‑89 is essentially required in HDACi-mediated p21 upregulation in hepetocellular carcinoma (HCC). Overexpression of ZBP-89 protein enhanced the lethal effectiveness of Trichostatin A (TSA). p53 mutant p53(G245D), but not p53(R249S), directly bound to ZBP-89 and prevented its translocation from cytoplasm to nucleus. Furthermore, p53(G245D) was shown to have a similar pattern of subcellular localization to ZBP-89 in tissues of HCC patients in Hong Kong. Functionally, the cytoplasmic accumulation of ZBP-89 by p53(G245D) significantly abrogated the induction of p21 caused by sodium butyrate (NaB) treatment and protected cells from TSA-induced death. The activations of several apoptotic proteins, such as Bid and PARP, were involved in p53(G245D)-mediated protection. Moreover, the resistance to HDACi in p53(G245D)-expressing cells was reversed by overexpression of ZBP-89. Taken together, these data suggest a potential mechanism via which mutant p53 enables tumor cells to resist chemotherapy and, therefore, establish a plausible link between mutant p53 binding to ZBP-89 and a decreased chemosensitivity of HCC cells.
Chris Z Y Zhang; George G Chen; Juanita L Merchant; Paul B S Lai
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-01-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-08-30     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  322-34     Citation Subset:  IM    
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT Hong Kong.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Butyrates / pharmacology*
Carcinoma, Hepatocellular / genetics,  metabolism*
Cell Line, Tumor / drug effects
Cell Survival / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
DNA-Binding Proteins / genetics,  metabolism*
Drug Resistance, Neoplasm
G1 Phase Cell Cycle Checkpoints / drug effects
Gene Expression
Histone Deacetylase Inhibitors / pharmacology*
Hydroxamic Acids / pharmacology*
Mutant Proteins / genetics,  metabolism*
Mutation, Missense
Protein Binding
Transcription Factors / genetics,  metabolism*
Tumor Suppressor Protein p53 / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Butyrates; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/DNA-Binding Proteins; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Mutant Proteins; 0/TP53 protein, human; 0/Transcription Factors; 0/Tumor Suppressor Protein p53; 0/ZNF148 protein, human; 3X2S926L3Z/trichostatin A

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