Abstract 3328: Targeted inactivation of EZH2 by CDF inhibits pancreatic tumor growth mediated by re-expression of lost miRNAs in tumors

EZH2 plays a critical role in the regulation of cell survival, proliferation and cancer stem cell (CSC) function, contributing to tumor aggressiveness. Increased expression of EZH2 has been found in human pancreatic cancer (PC); however, the mechanism(s) by which EZH2 mediates its biological effects is not known, and there is no avenue for inactivation of EZH2. In this study, we examined the effect of CDF, a novel Curcumin analogue, on tumor cell growth in vitro and in vivo and assessed whether the effect of CDF is due to inactivation of EZH2 and CSC function mediated by deregulation of microRNAs (miRNAs). We found that CDF decreased cell survival, clonogenicity, formation of pancreatospheres, cell migration and invasion, and attenuated CSC function in human PC cells, which was associated with inactivation of EZH2 expression and NF-κB activity, and increased expression of miRNAs such as let-7a, b, c, d, miR-26a, miR-101, miR-146a, and miR-200b, c. Further mechanistic studies showed that the re-expression of miR-101 led to decreased expression of EZH2 and EpCAM. Moreover, CDF inhibited tumor growth in a mouse orthotopic model of PC, which was associated with decreased expression of EZH2, Notch-1, CD44, EpCAM and Nanog, and increased expression of let-7, miR-26a and miR-101 in tumor remnant. From these results, we conclude that the inhibition of tumor growth and tumor cell aggressiveness by CDF is in part due to down-regulation of EZH2, which was mediated by up-regulation of specific miRNAs, suggesting that CDF could be useful for the prevention of tumor progression and/or treatment of PC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3328. doi:1538-7445.AM2012-3328