RRC ID |
47699
|
著者 |
Kajiura K, Masuda K, Naruto T, Kohmoto T, Watabnabe M, Tsuboi M, Takizawa H, Kondo K, Tangoku A, Imoto I.
|
タイトル |
Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma.
|
ジャーナル |
Oncotarget
|
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.
|
巻・号 |
8(2)
|
ページ |
2890-2905
|
公開日 |
2017-1-10
|
DOI |
10.18632/oncotarget.13761
|
PII |
13761
|
PMID |
27926516
|
PMC |
PMC5356850
|
MeSH |
Adaptor Proteins, Signal Transducing / genetics*
Adenocarcinoma / genetics*
Adenocarcinoma / metabolism
Adenocarcinoma / pathology*
Adenocarcinoma of Lung
Aged
Aged, 80 and over
Animals
Cell Cycle
Cell Line, Tumor
Cell Proliferation
CpG Islands
DNA Methylation*
Disease Models, Animal
Epigenesis, Genetic
Epigenomics / methods
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Silencing*
Genes, Tumor Suppressor*
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Male
Membrane Proteins / genetics*
Mice
Middle Aged
Neoplasm Staging
Promoter Regions, Genetic*
Sequence Analysis, DNA
Ubiquitin / metabolism
|
IF |
5.168
|
引用数 |
22
|
WOS 分野
|
CELL BIOLOGY
ONCOLOGY
|
リソース情報 |
ヒト・動物細胞 |
A549(RCB0098)
PC-3(RCB2145) |