title: Epigenetic silencing of diacylglycerol kinase gamma in colorectal cancer.
abstract: Diacylglycerol kinases (DGKs) are important regulators of cell signaling and have been implicated in human malignancies. Whether epigenetic alterations are involved in the dysregulation of DGKs in cancer is unknown, however. We therefore analyzed methylation of the promoter CpG islands of DGK genes in colorectal cancer (CRC) cell lines. We found that DGKG, which encodes DGKγ, was hypermethylated in all CRC cell lines tested (n = 9), but was not methylated in normal colonic tissue. Correspondingly, DGKG expression was suppressed in CRC cell lines but not in normal colonic tissue, and was restored in CRC cells by treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC). DGKG methylation was frequently observed in primary CRCs (73/141, 51.8%) and was positively associated with KRAS and BRAF mutations and with the CpG island methylator phenotype (CIMP). DGKG methylation was also frequently detected in colorectal adenomas (89 of 177, 50.3%), which suggests it is an early event during colorectal tumorigenesis. Ectopic expression of wild-type DGKγ did not suppress CRC cell proliferation, but did suppress cell migration and invasion. Notably, both constitutively active and kinase-dead DGKγ mutants exerted inhibitory effects on CRC cell proliferation, migration and invasion, and the wild-type and mutant forms of DGKγ all suppressed Rac1 activity in CRC cells. These data suggest DGKG may play a tumor suppressor role in CRC.
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kai
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Digestive Disease Center, Akira Red Cross Hospital, Akita, Japan.
authors.forename: Hiro-O
authors.initials: HO
authors.lastname: Yamano
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Niinuma
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitajima
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Toyota
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tomo
authors.initials: T
authors.lastname: Hatahira
authors.affiliation: Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakase
authors.affiliation: Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiromu
authors.identifier: 0000-0001-9635-3238
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D019852:Diacylglycerol Kinase / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D019852:Diacylglycerol Kinase
keywords: DGKG; DNA methylation; colorectal cancer; diacylglycerol kinase