Document Detail

Wnt antagonist DKK1 acts as a tumor suppressor gene that induces apoptosis and inhibits proliferation in human renal cell carcinoma.
MedLine Citation:
PMID:  20549706     Owner:  NLM     Status:  MEDLINE    
The functional significance of Wnt antagonist DKK1 has not been investigated in renal cell carcinoma (RCC). Therefore, we hypothesized that DKK1 may be a tumor suppressor gene and is epigenetically silenced, thus decreased DKK1 may cause progression of RCC. To assess the function of DKK1, we established stable DKK1 transfected cells and monitored them regarding cell viability, colony formation, apoptosis, cell cycle, and invasive capability. RCC cell lines had decreased levels of DKK1, which were increased after treatment with 5-Aza-2'-deoxycytidine and trichostatin A. In chromatin immunoprecipitation assay, the level of dimethyl H3K9 and trimethyl H3K27 was decreased after 5-Aza-2'-deoxycytidine/trichostatin A treatment in RCC cell lines. Increased methylation was also associated with higher pathological stages in primary RCC tissues. T-cell factor/lymphoid enhancer factor activity and nuclear beta-catenin expression were not changed in DKK1 transfectants. Also the expression of cyclinD1 and c-Myc was not changed in DKK1 transfectants. These results suggest that DKK1 may not be involved in the beta-catenin dependent pathway. We also evaluated the expression of various related genes. Cleaved caspase3, p53, p21 and puma expression were significantly upregulated in the DKK1 transfected cells. The population of apoptotic cells was increased in stable DKK1 cells and tumor growth suppression was also observed in nude mice with DKK1 transfected cells. In conclusion, this is the first report to show that DKK1 expression is epigenetically silenced in kidney cancer and its reexpression induces apoptosis and cell cycle arrest in RCC.
Hiroshi Hirata; Yuji Hinoda; Koichi Nakajima; Ken Kawamoto; Nobuyuki Kikuno; Koji Ueno; Soichiro Yamamura; Mohd S Zaman; Gaurav Khatri; Yi Chen; Sharanjot Saini; Shahana Majid; Guoren Deng; Nobuhisa Ishii; Rajvir Dahiya
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  128     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-02-23     Completed Date:  2011-04-18     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1793-803     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 UICC.
Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
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MeSH Terms
Antimetabolites, Antineoplastic / pharmacology
Apoptosis Regulatory Proteins / genetics,  metabolism
Azacitidine / analogs & derivatives,  pharmacology
Blotting, Western
Carcinoma, Renal Cell / genetics,  metabolism,  pathology*
Caspase 3 / genetics,  metabolism
Cell Proliferation*
Chromatin Immunoprecipitation
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism
DNA Methylation
Epigenesis, Genetic
Genes, Tumor Suppressor*
Hydroxamic Acids / pharmacology
Immunoenzyme Techniques
Intercellular Signaling Peptides and Proteins / physiology*
Kidney Neoplasms / genetics,  metabolism,  pathology*
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins / genetics,  metabolism
RNA, Messenger / genetics
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics,  metabolism
Wnt Proteins / antagonists & inhibitors*
Grant Support
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Apoptosis Regulatory Proteins; 0/BBC3 protein, human; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/DKK1 protein, human; 0/Hydroxamic Acids; 0/Intercellular Signaling Peptides and Proteins; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/Wnt Proteins; 320-67-2/Azacitidine; 3X2S926L3Z/trichostatin A; 776B62CQ27/decitabine; EC 3.4.22.-/Caspase 3

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