Abstract 2191: The Wnt/DVL signaling antagonist DACT2 is a pro-apoptotic tumor suppressor epigenetically silenced in multiple tumors and inhibits tumor cell proliferation and migration

Abstract

Abstract Wnt/DVL/β-catenin signaling pathway is aberrantly activated in a wide range of human cancers which frequently involves the disruption of its negative regulators, hence we would like to identify tumor suppressor as the antagonist to this signaling pathway. We identified a DACT (Dpr/Frodo) family member DACT2 as a downregulated gene in human tumors. Further epigenetic study revealed that, in contrast to its broad expression in normal tissues and cell lines, DACT2 is silenced or downregulated in multiple tumor cell lines including nasopharyngeal (NPC), esophageal (ESCC), gastric, colorectal (CRC), breast, lung, renal (RCC), hepatocellular (HCC), prostate and cervix carcinomas, due to its promoter methylation which could be reversed by pharmacological demethylation. DACT2 promoter methylation was also frequently detected in multiple primary tumors, suggesting that DACT2 is a potential tumor marker. DACT2 encodes a cytoplasm protein localized in endosome. Ectopic expression of DACT2 dramatically inhibited tumor cell colony formation in silenced tumor cell lines, mainly through inducing apoptosis. DACT2 interacts and downregulates Dishevelled (DVL) protein, thus protecting glycogen synthase kinase 3β (GSK-3β) from inactivation by WNT/DVL and allowing GSK-3β to form a complex with Axin and APC to promote the phosphorylation and proteasomal degradation of β-catenin. Overexpression of DACT2 disrupted β-catenin activation and accumulation in nucleus, thus preventing its binding to transcription factors of the Lef/Tcf family. This caused the downregulation of target oncogenes such as c-Myc, CCND1 and fibronectin and the inhibition of tumor cell proliferation and migration. We also observed that DACT2 could upregulate epithelial cell marker E-cadherin, and modulate Akt/GSK-3β/β-catenin signaling pathway, another pathway involved in tumor cell epithelial mesenchymal transition. Our data demonstrate that DACT2 is a functional tumor suppressor epigenetically silenced in multiple tumors which acts as a negative regulator of the Wnt/DVL/β-Catenin pathway, and could be a promising biomarker for human tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2191. doi:10.1158/1538-7445.AM2011-2191