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.
Copyright © 2011 Wiley-Liss, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis*
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Blotting, Western
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism*
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Carcinoma, Renal Cell / pathology*
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Cell Cycle
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Cell Proliferation
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Cells, Cultured
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Chemokines
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Chromatin Immunoprecipitation
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CpG Islands
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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DNA Methylation
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Epigenesis, Genetic
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Histones / metabolism
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Humans
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Immunoenzyme Techniques
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Intercellular Signaling Peptides and Proteins / genetics*
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Intercellular Signaling Peptides and Proteins / metabolism*
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Kidney / metabolism
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Kidney / pathology
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism*
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Luciferases / metabolism
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Mice
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Mice, Nude
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Wnt Proteins / antagonists & inhibitors*
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Wnt Proteins / metabolism
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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CDKN1A protein, human
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Chemokines
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Cyclin-Dependent Kinase Inhibitor p21
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DKK3 protein, human
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Histones
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Intercellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Wnt Proteins
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beta Catenin
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Luciferases