Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma.
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.
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT Hong Kong.
Chris Z Y
CZ
Zhang
George G
GG
Chen
Juanita L
JL
Merchant
Paul B S
PB
Lai
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002087:Butyrates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D002087:Butyrates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050505:Mutant Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C110951:ZNF148 protein, human; C012589:trichostatin A