title: Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma.
abstract: In this study, we aimed to identify novel drivers that would be epigenetically altered through aberrant methylation in early-stage lung adenocarcinoma (LADC), regardless of the presence or absence of tobacco smoking-induced epigenetic field defects. Through genome-wide screening for aberrantly methylated CpG islands (CGIs) in 12 clinically uniform, stage-I LADC cases affecting six non-smokers and six smokers, we identified candidate tumor-suppressor genes (TSGs) inactivated by hypermethylation. Through systematic expression analyses of those candidates in panels of additional tumor samples and cell lines treated or not treated with 5-aza-deoxycitidine followed by validation analyses of cancer-specific silencing by CGI hypermethylation using a public database, we identified TRIM58 as the most prominent candidate for TSG. TRIM58 was robustly silenced by hypermethylation even in early-stage primary LADC, and the restoration of TRIM58 expression in LADC cell lines inhibited cell growth in vitro and in vivo in anchorage-dependent and -independent manners. Our findings suggest that aberrant inactivation of TRIM58 consequent to CGI hypermethylation might stimulate the early carcinogenesis of LADC regardless of smoking status; furthermore, TRIM58 methylation might be a possible early diagnostic and epigenetic therapeutic target in LADC.
authors.affiliation: Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.|Department of Thoracic, Endocrine and Oncological Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kajiura
authors.affiliation: Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Naruto
authors.affiliation: Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kohmoto
authors.affiliation: Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Watabnabe
authors.affiliation: Department of Thoracic, Endocrine and Oncological Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Department of Thoracic, Endocrine and Oncological Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takizawa
authors.affiliation: Department of Oncological Medical Services, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Thoracic, Endocrine and Oncological Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tangoku
authors.affiliation: Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C114030:TRAT1 protein, human; D025801:Ubiquitin
keywords: TRIM58; early-stage lung adenocarcinoma; methylation; smoking status; tumor suppressor gene