Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma.
Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma.
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DOI：
10.18632/oncotarget.13761
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发表时间：
2017-01-10
期刊：
影响因子：
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通讯作者：
Imoto I
中科院分区：
文献类型：
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作者：
Kajiura K;Masuda K;Naruto T;Kohmoto T;Watabnabe M;Tsuboi M;Takizawa H;Kondo K;Tangoku A;Imoto I
在这项研究中，我们的目的是确定新的驱动程序，将通过异常甲基化在早期肺腺癌（LADC）的表观遗传改变，无论是否存在烟草吸烟诱导的表观遗传领域的缺陷。通过全基因组筛选异常甲基化的CpG岛（CGIs）在12个临床统一，I期LADC的情况下，影响6个非吸烟者和6个吸烟者，我们确定了候选的肿瘤抑制基因（TSGs）失活的超甲基化。通过在用5-氮杂-脱氧胞苷处理或未处理的其他肿瘤样品和细胞系的组中对这些候选物进行系统表达分析，然后使用公共数据库通过CGI超甲基化对癌症特异性沉默进行验证分析，我们将TRIM 58鉴定为TSG的最突出的候选物。TRIM 58是强大的沉默，甚至在早期阶段的主要LADC的超甲基化，和TRIM 58表达的恢复在LADC细胞系抑制细胞生长在体外和体内的锚定依赖性和非依赖性的方式。我们的研究结果表明，异常失活的TRIM 58随之CGI超甲基化可能会刺激LADC的早期癌变，无论吸烟状态;此外，TRIM 58甲基化可能是一个可能的早期诊断和表观遗传治疗靶点LADC。
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.