Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma

Chris Z.Y. Zhang, George G. Chen, Juanita L. Merchant, Paul B.S. Lai

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)322-334
Number of pages13
JournalCell Cycle
Volume11
Issue number2
DOIs
StatePublished - Jan 15 2012
Externally publishedYes

Keywords

  • Apoptosis
  • HCC
  • HDACi
  • p53 mutant
  • ZBP-89

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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