Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT Hong Kong.
Cell Cycle. 2012 Jan 15;11(2):322-34. doi: 10.4161/cc.11.2.18758.
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.
锌指转录因子 ZBP-89 参与组蛋白去乙酰化酶抑制剂（HDACi）介导的癌细胞生长停滞和凋亡。p53 突变体可能与转录调节 p21(Waf1)（p21）的 ZBP-89 相互作用。然而，这种相互作用及其在癌症治疗中的后果知之甚少。在这项研究中，我们证明 ZBP-89 在 HDACi 介导的肝癌（HCC）中 p21 的上调中是必需的。ZBP-89 蛋白的过表达增强了 Trichostatin A（TSA）的致死效力。p53 突变体 p53(G245D)，而不是 p53(R249S)，直接与 ZBP-89 结合，并阻止其从细胞质易位到细胞核。此外，p53(G245D)在香港 HCC 患者的组织中显示出与 ZBP-89 相似的亚细胞定位模式。功能上，p53(G245D)通过细胞质中 ZBP-89 的积累，显著阻断了丁酸钠（NaB）处理引起的 p21 诱导，并保护细胞免受 TSA 诱导的死亡。几种凋亡蛋白的激活，如 Bid 和 PARP，参与了 p53(G245D)介导的保护。此外，p53(G245D)表达细胞对 HDACi 的耐药性通过 ZBP-89 的过表达而逆转。综上所述，这些数据表明了一种潜在的机制，即突变型 p53 使肿瘤细胞能够抵抗化疗，因此建立了突变型 p53 与 ZBP-89 结合和 HCC 细胞化疗敏感性降低之间的合理联系。
