title: 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.
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.
authors.affiliation: Department of Internal Medicine, Institute of Gastroenterology,                     Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Shin
authors.forename: Jie-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Yeo Song
authors.initials: YS
authors.lastname: Lee
authors.forename: Yong Chan
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077209:Decitabine; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000970:Antineoplastic Agents; D001374:Azacitidine; D002087:Butyrates; D015254:DNA Modification Methylases; D000077209:Decitabine; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human