Abstract 333: ZBP-89 downregulates histone deacetylase 3 (HDAC3) through inhibition of I kappa B in hepatocelluar carcinoma (HCC)

Abstract

Abstract Background Histone deacetylase 3 (HDAC3) is frequently overexpressed in hepatocelluar carcinoma (HCC) and its inhibition enhances the efficacy of anti-HCC chemotherapy. ZBP-89 is known to induce apoptosis via an increase of pro-apoptotic Bak. But the relationship between ZBP-89 and HDAC3 is largely unknown. Method Human HCC cell lines PLC/PRF/5 and HepG2 were cultured in Minimum Essential Medium and treated with various agents to modulate NF-κB. These agents included CAY10576 and MG132 (which are inhibitors of I kappa B (IκB) degradation) as well as SN50 (an inhibitor of p65/p50 translocation). A xenograft tumor model was established by subcutaneous injection of HCC PLC/PRF/5 cells into nude mice and this model was used to confirm data obtained in HCC cell culture experiments. The expressions of relevant proteins were measured by Western blot or/and immunohistochemical staining. Results Our results showed that ZBP-89 reduced the expression of HDAC3 in HCC cells. ZBP-89 could form a complex with IκB and induce the phosphorylation of IκB, which inhibited IκB. Furthermore, ZBP-89-mediated HDAC3 reduction could be suppressed by IκB degradation inhibitors CAY10576 and MG132 but not NF-κB subunit p65/p50 translocation inhibitor SN50. These findings indicate that IκB decreases rather than increases the activity of NF-κB; and such may be involved in the ZBP-89-mediated HDAC3 reduction. In the HCC xenograft model, it was confirmed that the expression of HDAC3, measured by immunohistochemical staining and Western blot, was reduced in HCC with ZBP-89 overexpression, compared with the control. In contrast to HDAC3, ZBP-89 enhanced the expression of Bak. Conclusion ZBP-89 downregulates HDAC3 by decreasing IκB rather than elevating activity of NF-κB. This novel pathway identified helps us understand more the mechanism of ZBP-89-mediated inhibition of HCC. Citation Format: Paul B. Lai, Cai-Guo Ye, Liping Liu, Ming-Liang He, Rocky Ho, George G. Chen. ZBP-89 downregulates histone deacetylase 3 (HDAC3) through inhibition of I kappa B in hepatocelluar carcinoma (HCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 333. doi:10.1158/1538-7445.AM2014-333