RRC ID 47699
Author Kajiura K, Masuda K, Naruto T, Kohmoto T, Watabnabe M, Tsuboi M, Takizawa H, Kondo K, Tangoku A, Imoto I.
Title Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma.
Journal 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.
Volume 8(2)
Pages 2890-2905
Published 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
Times Cited 22
Human and Animal Cells A549(RCB0098) PC-3(RCB2145)