title: IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype.
abstract: A subset of colorectal cancers (CRCs) show simultaneous methylation of multiple genes; these tumors have the CpG island methylator phenotype (CIMP). CRCs with CIMP show a specific pattern of genetic alterations, including a high frequency of BRAF mutations and a low frequency of p53 mutations. We therefore hypothesized that genes inactivated by DNA methylation are involved in the BRAF- and p53-signaling pathways. Among those, we examined the epigenetic inactivation of insulin-like growth factor-binding protein 7 (IGFBP7) expression in CRCs. We found that in CRC cell lines, the silencing of IGFBP7 expression was correlated with high levels of DNA methylation and low levels of histone H3K4 methylation. Luciferase and chromatin immunoprecipitation assays in unmethylated cells revealed that p53 induces expression of IGFBP7 upon binding to a p53 response element within intron 1 of the gene. Treating methylated CRC cell lines with 5-aza-2'-deoxycytidine restored p53-induced IGFBP7 expression. Levels of IGFBP7 methylation were also significantly higher in primary CRC specimens than in normal colonic tissue (P < 0.001). Methylation of IGFBP7 was correlated with BRAF mutations, an absence of p53 mutations and the presence of CIMP. Thus, epigenetic inactivation of IGFBP7 appears to play a key role in tumorigenesis of CRCs with CIMP by enabling escape from p53-induced senescence.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, South 1,West 17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Igarashi
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kai
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akashi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.forename: Lanlan
authors.initials: L
authors.lastname: Shen
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D016384:Consensus Sequence; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D000077209:Decitabine; D020868:Gene Silencing; D016158:Genes, p53; D006657:Histones / Q000235:genetics; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D004273:DNA, Neoplasm; D006657:Histones; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C102529:insulin-like growth factor binding protein-related protein 1; D000077209:Decitabine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D001374:Azacitidine