Inactivation of the 14-3-3 sigma gene is associated with 5' CpG island hypermethylation in human cancers.
The cell cycle checkpoint plays an important role in maintaining the integrity of cells. Recently, one of the 14-3-3 protein family members, 14-3-3sigma, was shown to be regulated by p53 and to play a role in the G2-M-phase checkpoint. To determine whether 14-3-3sigma is inactivated in human cancers, the methylation status of the 5' region of 14-3-3sigma was investigated in a series of gastric, colorectal, and hepatocellular cancer cell lines. Of 22 cell lines examined, 6 showed aberrant methylation. The methylation status of 14-3-3sigma was found to be correlated with loss of expression, which was restored by 5-aza-2'-deoxycytidine treatment. Furthermore, normal G2 arrest after DNA damage was not demonstrated in the cell lines with methylation. In primary gastric cancers, 14-3-3sigma hypermethylation was observed frequently in 26 of 60 (43%) cases and observed more frequently in poorly differentiated adenocarcinomas (P = 0.0017). Our findings suggest that 14-3-3sigma is inactivated by aberrant methylation of the 5' region in various human cancers and that it might play an important role in the development of undifferentiated gastric cancers.
Suzuki
H
H
First Department of Internal Medicine, Sapporo Medical University, Japan.
Itoh
F
F
Toyota
M
M
Kikuchi
T
T
Kakiuchi
H
H
Imai
K
K
D048948:14-3-3 Proteins; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014408:Biomarkers, Tumor; D002453:Cell Cycle / Q000502:physiology; D018899:CpG Islands / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000077209:Decitabine; D004591:Electrophoresis, Polyacrylamide Gel; D005092:Exonucleases; D005095:Exoribonucleases; D005453:Fluorescence; D016195:G2 Phase / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology*; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins; D009368:Neoplasm Transplantation; D009690:Nucleic Acid Conformation; D016133:Polymerase Chain Reaction / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism; D013447:Sulfites; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011506:Proteins; D013447:Sulfites; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D001374:Azacitidine; C042345:hydrogen sulfite