Journal
ONCOTARGET
Volume 8, Issue 2, Pages 2890-2905Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13761
Keywords
TRIM58; early-stage lung adenocarcinoma; tumor suppressor gene; methylation; smoking status
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Funding
- JSPS KAKENHI Grant [26293304, 16K15618, 24590943, 15K19620, 25861245]
- Grants-in-Aid for Scientific Research [15K08949, 24590943, 25861245, 16K15618, 26293304, 15K19620] Funding Source: KAKEN
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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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