title: TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells.
abstract: Aberrant DNA methylation is commonly observed in colorectal cancer (CRC), but the underlying mechanism is not fully understood. 5-hydroxymethylcytosine levels and TET1 expression are both reduced in CRC, while epigenetic silencing of TET1 is reportedly associated with the CpG island methylator phenotype. In the present study, we aimed to clarify the relationship between loss of TET1 and aberrant DNA methylation in CRC. Stable TET1 knockdown clones were established using Colo320DM cells, which express high levels of TET1, and HCT116 cells, which express TET1 at a level similar to that in normal colonic tissue. Infinium HumanMethylation450 BeadChip assays revealed increased levels of 5-methylcytosine at more than 10,000 CpG sites in TET1-depleted Colo320DM cells. Changes in DNA methylation were observed at various positions within the genome, including promoters, gene bodies and intergenic regions, and the altered methylation affected expression of a subset of genes. By contrast, TET1 knockdown did not significantly affect DNA methylation in HCT116 cells. However, TET1 depletion was associated with attenuated effects of 5-aza-2'-deoxycytidine on gene expression profiles in both cell lines. These results suggest that loss of TET1 may induce aberrant DNA methylation and may attenuate the effect of 5-aza-2'-deoxycytidine in CRC cells.
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.
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.|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: 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: Medical Genome Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Medical Genome Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
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 Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiromu
authors.identifier: http://orcid.org/0000-0001-9635-3238
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000077209:Decitabine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D001374:Azacitidine