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Change in gene expression profiles of secreted frizzled-related proteins (SFRPs) by sodium butyrate in gastric cancers: induction of promoter demethylation and histone modification causing inhibition of Wnt signaling.

Authors
 Hyunsoo Shin  ;  Jie-Hyun Kim  ;  Yeo Song Lee  ;  Yong Chan Lee 
Citation
 International Journal of Oncology, Vol.40(5) : 1533-1542, 2012 
Journal Title
 International Journal of Oncology 
ISSN
 1019-6439 
Issue Date
2012
MeSH
Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/pharmacology* ; Apoptosis/drug effects ; Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Butyrates/pharmacology* ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Methylation/drug effects* ; DNA Modification Methylases/antagonists & inhibitors ; DNA Modification Methylases/metabolism ; Down-Regulation ; Epigenesis, Genetic/drug effects ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects* ; Genes, Reporter ; Histone Deacetylase Inhibitors/pharmacology* ; Histones/metabolism* ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism* ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism* ; Middle Aged ; Promoter Regions, Genetic/drug effects* ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism* ; Stomach Neoplasms/pathology ; Transfection ; Wnt Signaling Pathway/drug effects* ; beta Catenin/metabolism
Keywords
Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/pharmacology* ; Apoptosis/drug effects ; Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Butyrates/pharmacology* ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Methylation/drug effects* ; DNA Modification Methylases/antagonists & inhibitors ; DNA Modification Methylases/metabolism ; Down-Regulation ; Epigenesis, Genetic/drug effects ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects* ; Genes, Reporter ; Histone Deacetylase Inhibitors/pharmacology* ; Histones/metabolism* ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism* ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism* ; Middle Aged ; Promoter Regions, Genetic/drug effects* ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism* ; Stomach Neoplasms/pathology ; Transfection ; Wnt Signaling Pathway/drug effects* ; beta Catenin/metabolism
Abstract
Activation of Wnt signaling without mutation of β-catenin or APC occurs frequently in human gastric cancers. Secreted frizzled-related protein (SFRP), a negative modulator of the Wnt signaling pathway, are frequently inactivated in human gastric cancers. Inhibition of SFRP gene expression may account for the Wnt/β-catenin activation in human gastric cancer. However, the molecular mechanisms of silencing of SFRP genes are not fully understood. Sodium butyrate, a histone deacetylase (HDAC) inhibitor, is known to exhibit anti-cancer effects partly through the differentiation of various cancer cells. In the present study, we investigated: i) the relationship between the silencing of SFRP genes and Wnt signaling; ii) the mechanism of sodium butyrate mediated epigenetic regulation of SFRPs expression in human gastric cancer. We observed that nuclear β-catenin was significantly increased in gastric cancer tissues as compared to adjacent non-cancerous tissues. Nuclear β-catenin accumulation and SFRP promoter methylation in human gastric cancer cells were noted. Treatment with the DNA methyltransferase inhibitor, 5'-Aza-2-deoxycytidine (5'-Aza-dC) rapidly restored SFRPs expression. Sodium butyrate (NaB) induced demethylation and histone modification at the promoter region of SFRP1/2 restoring the SFRP expression in human gastric cancer cells. Analysis of general expression revealed that overexpression of SFRPs repressed Wnt target gene expression and induced changes in the proliferation and apoptosis related genes in human gastric cancer cells. These data suggest that aberrant epigenetic modification of SFRP genes is one of the major mechanisms by which Wnt signaling is activated in human gastric cancer cells and sodium butyrate may modulate the SFRP1/2 expression through histone modification and promoter demethylation causing anti-tumor effects.
Full Text
http://www.spandidos-publications.com/ijo/40/5/1533
DOI
22246241
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
Yonsei Authors
Kim, Jie-Hyun(김지현) ORCID logo https://orcid.org/0000-0002-9198-3326
Shin, Hyun Soo(신현수)
Lee, Yeo Song(이여송)
Lee, Yong Chan(이용찬) ORCID logo https://orcid.org/0000-0001-8800-6906
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/90505
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