title: A genomic screen for long noncoding RNA genes epigenetically silenced by aberrant DNA methylation in colorectal cancer.
abstract: Long noncoding RNAs (lncRNAs) have emerged as key components in multiple cellular processes, although their physiological and pathological functions are not fully understood. To identify cancer-related lncRNAs, we screened for those that are epigenetically silenced in colorectal cancer (CRC). Through a genome-wide analysis of histone modifications in CRC cells, we found that the transcription start sites (TSSs) of 1,027 lncRNA genes acquired trimethylation of histone H3 lysine 4 (H3K4me3) after DNA demethylation. Integrative analysis of chromatin signatures and the DNA methylome revealed that the promoter CpG islands (CGIs) of 66 lncRNA genes contained cancer-specific methylation. By validating the expression and methylation of lncRNA genes in CRC cells, we ultimately identified 20 lncRNAs, including ZNF582-AS1, as targets of epigenetic silencing in CRC. ZNF582-AS1 is frequently methylated in CRC cell lines (87.5%), primary CRCs (77.2%), colorectal adenomas (44.7%) and advanced adenomas (87.8%), suggesting that this methylation is an early event during colorectal tumorigenesis. Methylation of ZNF582-AS1 is associated with poor survival of CRC patients, and ectopic expression of ZNF582-AS1 suppressed colony formation by CRC cells. Our findings offer insight into the association between epigenetic alterations and lncRNA dysregulation in cancer and suggest that ZNF582-AS1 may be a novel tumor-suppressive lncRNA.
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kumegawa
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.|PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.|Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ashida
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitajima
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuyada
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.|Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Niinuma
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kai
authors.affiliation: Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.
authors.forename: Hiro-O
authors.initials: HO
authors.lastname: Yamano
authors.affiliation: Department of Diagnostic Pathology, Iwate Medical University, Iwate, 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, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.affiliation: Center for Medical Innovation, The Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm