The Hypomethylation Agent Bisdemethoxycurcumin Acts on the WIF-1 Promoter, Inhibits the Canonical Wnt Pathway and Induces Apoptosis in Human Non-Small-Cell Lung Cancer

Y.-L.      Liu; H.-P.      Yang; X.-D.      Zhou; L.      Gong; C.-L.      Tang; H.-J.      Wang

doi:10.2174/156800911798073041

Abstract

Hypermethylation of the Wnt inhibitory factor-1 (WIF-1) promoter has been implicated in the overactivation of the Wnt pathway in human lung cancer. Curcuminoids exert anti-cancer effects and have been reported to act as hypomethylating agents. Previously, we have investigated and compared the demethylation effects of three curcuminoids and observed that bisdemethoxycurcumin exhibited the strongest demethylation potency. In this study, we used lung cancer cell lines with WIF-1 promoter hypermethylated as a model to study the demethylating effect of bisdemethoxycurcumin on WIF-1 restoration, Wnt signaling activity and cell death. Bisdemethoxycurcumin directly suppressed the activity of DNA methyltransferase-1 (DNMT1) but did not influence DNMT1 expression. In addition, it induced WIF-1 promoter demethylation and protein re-expression. WIF-1 restoration in lung cancer cells down-regulated nuclear β-catenin and the canonical Wnt cascade. Furthermore, we also showed that down-regulation of Wnt signaling by WIF-1 was required for bisdemethoxycurcumin-induced apoptosis in certain lung cancer cell types. This report is the first to show that bisdemethoxycurcumin induces apoptosis by reactivating WIF-1 from a silenced state. Our results provide new insights into the anti-cancer actions of bisdemethoxycurcumin.

Keywords: Apoptosis, bisdemethoxycurcumin, lung neoplasms, promoter demethylation, Wnt inhibitory factor-1, DNA methyltransferase-1, Epidermal growth factor receptor, Non-small-cell lung cancer, TCF response elements, Wingless/int