Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer.
Aberrant methylation of a sodium co-transporter, solute carrier family 5 member 8 gene (SLC5A8), has been detected in a subset of colorectal cancers, suggesting SLC5A8 may also serve as a tumor suppressor. To further investigate the role of epigenetic inactivation of SLC5A8 expression in gastric cancer, we determined the methylation status of the SLC5A8 5' CpG island (CGI) in a panel of gastric cancer cell lines and primary gastric cancers. We detected methylation of the 5'CGI in ten of twelve gastric cancer cell lines, and five of those showed dense methylation, which correlated with the absence of SLC5A8 transcription. Aberrant methylation of SLC5A8 was also detected in 23 of 71 (30%) primary gastric cancers, indicating that epigenetic inactivation of SLC5A8 is not a cell-line-specific phenomenon. SLC5A8 expression was restored in methylated cell lines by treatment with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor. In addition, chromatin immunoprecipitation assays showed that acetylation of histone H3 in the 5' region of the gene correlated directly with SLC5A8 expression and inversely with DNA methylation. It thus appears that aberrant methylation of its 5'CGI and histone deacetylation play key roles in silencing SLC5A8 expression in gastric cancers.
Ueno
Masako
M
First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan.
Toyota
Minoru
M
Akino
Kimishige
K
Suzuki
Hiromu
H
Kusano
Masanobu
M
Satoh
Ayumi
A
Mita
Hiroaki
H
Sasaki
Yasushi
Y
Nojima
Masanori
M
Yanagihara
Kazuyoshi
K
Hinoda
Yuji
Y
Tokino
Takashi
T
Imai
Kohzoh
K
D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D027501:Monocarboxylic Acid Transporters; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured
D027682:Cation Transport Proteins; D027501:Monocarboxylic Acid Transporters; C476760:SLC5A8 protein, human