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Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma

2016; Impact Journals LLC; Volume: 8; Issue: 2 Linguagem: Inglês

10.18632/oncotarget.13761

1949-2553

Koichiro Kajiura, Kiyoshi Masuda, Takuya Naruto, Tomohiro Kohmoto, Miki Watabnabe, Mitsuhiro Tsuboi, Hiromitsu Takizawa, Kazuya Kondo, Akira Tangoku, Issei Imoto,

Peptidase Inhibition and Analysis

// Koichiro Kajiura 1, 2, * , Kiyoshi Masuda 1, * , Takuya Naruto 1 , Tomohiro Kohmoto 1 , Miki Watabnabe 1 , Mitsuhiro Tsuboi 2 , Hiromitsu Takizawa 2 , Kazuya Kondo 3 , Akira Tangoku 2 , Issei Imoto 1 1 Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan 2 Department of Thoracic, Endocrine and Oncological Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan 3 Department of Oncological Medical Services, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan * These authors contributed equally to this work Correspondence to: Issei Imoto, email: issehgen@tokushima-u.ac.jp Keywords: TRIM58, early-stage lung adenocarcinoma, tumor suppressor gene, methylation, smoking status Received: August 26, 2016 Accepted: November 22, 2016 Published: December 01, 2016 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.