TY - JOUR
T1 - Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma
AU - Zhang, Chris Z.Y.
AU - Chen, George G.
AU - Merchant, Juanita L.
AU - Lai, Paul B.S.
N1 - Funding Information: This work was supported by the Research Grants Council of the Hong Kong SAR. No. CUHK4551/05M and CUHK 462009 to P.B.S.L. and G.G.C. and US Public Health Service grant R01-DK055732 to J.L.M.
PY - 2012/1/15
Y1 - 2012/1/15
N2 - 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 p21Waf1 (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 p53G245D, but not p53R249S, directly bound to ZBP-89 and prevented its translocation from cytoplasm to nucleus. Furthermore, p53G245D 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 p53G245D 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 p53G245D-mediated protection. Moreover, the resistance to HDACi in p53G245D-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.
AB - 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 p21Waf1 (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 p53G245D, but not p53R249S, directly bound to ZBP-89 and prevented its translocation from cytoplasm to nucleus. Furthermore, p53G245D 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 p53G245D 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 p53G245D-mediated protection. Moreover, the resistance to HDACi in p53G245D-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.
KW - Apoptosis
KW - HCC
KW - HDACi
KW - ZBP-89
KW - p53 mutant
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U2 - 10.4161/cc.11.2.18758
DO - 10.4161/cc.11.2.18758
M3 - Article
C2 - 22214764
SN - 1538-4101
VL - 11
SP - 322
EP - 334
JO - Cell Cycle
JF - Cell Cycle
IS - 2
ER -