Research Papers:

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

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

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Oncotarget. 2017; 8:2890-2905. https://doi.org/10.18632/oncotarget.13761

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Koichiro Kajiura1,2,*, Kiyoshi Masuda1,*, Takuya Naruto1, Tomohiro Kohmoto1, Miki Watabnabe1, Mitsuhiro Tsuboi2, Hiromitsu Takizawa2, Kazuya Kondo3, Akira Tangoku2, Issei Imoto1

1Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

2Department of Thoracic, Endocrine and Oncological Surgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

3Department 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: [email protected]

Keywords: TRIM58, early-stage lung adenocarcinoma, tumor suppressor gene, methylation, smoking status

Received: August 26, 2016     Accepted: November 22, 2016     Published: December 01, 2016


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.

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