Wnt antagonist DICKKOPF-3 (Dkk-3) induces apoptosis in human renal cell carcinoma

Koji Ueno, Hiroshi Hirata, Shahana Majid, Yi Chen, Mohd S Zaman, Z Laura Tabatabai, Yuji Hinoda, Rajvir Dahiya
Molecular Carcinogenesis 2011, 50 (6): 449-57
The Wnt signaling pathway is activated in most cancers while Wnt antagonist genes are inactivated. However, the functional significance and mechanisms of inactivation of Wnt antagonist Dkk-3 gene in renal cell carcinoma (RCC) has not been reported. In this study, we examined potential epigenetic mechanisms regulating Dkk-3 expression in RCC cells and whether Dkk-3 expression affects cell growth and apoptosis. The expression of Dkk-3 is regulated by histone modification rather than CpG island DNA methylation in renal cancer cells. Renal cancer cell proliferation was significantly inhibited and apoptosis was promoted in Dkk-3 transfected renal cancer cells. Dkk-3 did not inhibit the Wnt/beta-catenin signaling pathway but induced apoptosis via the noncanonical JNK pathway in renal cancer cells. Expression of p21, MDM-2, and Puma genes were increased after transfecting RCC cell lines with a Dkk-3 expression plasmid. Overexpression of Dkk-3 induced G(0)/G(1) arrest together with an increase in p21 expression. Growth of stable Dkk-3 transfected cells in nude mice was decreased compared to controls. Our data show for the first time that mRNA expression of Dkk-3 is regulated by histone modification and that Dkk-3 inhibits renal cancer growth through modulation of cell cycle and apoptotic pathways.

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