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Wnt antagonist DICKKOPF‐3 (Dkk‐3) induces apoptosis in human renal cell carcinoma
Author(s) -
Ueno Koji,
Hirata Hiroshi,
Majid Shahana,
Chen Yi,
Zaman Mohd S.,
Tabatabai Z. Laura,
Hinoda Yuji,
Dahiya Rajvir
Publication year - 2011
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20729
Subject(s) - wnt signaling pathway , biology , apoptosis , cancer research , transfection , cell growth , cell cycle , cancer cell , signal transduction , lrp5 , cancer , microbiology and biotechnology , cell culture , biochemistry , genetics
Abstract 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. © 2011 Wiley‐Liss, Inc.