Methylation of Wnt7a is modulated by DNMT1 and cigarette smoke condensate in non-small cell lung cancer.
Methylation of Wnt7a is modulated by DNMT1 and cigarette smoke condensate in non-small cell lung cancer.
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DOI：
10.1371/journal.pone.0032921
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Winn RA
中科院分区：
文献类型：
--
作者：
Tennis MA;Vanscoyk MM;Wilson LA;Kelley N;Winn RA
Wnt7a是一种已知的肿瘤抑制因子，在非小细胞肺癌中丢失，但丢失的机制尚未确定。启动子区域甲基化已被确定为非小细胞肺癌中肿瘤抑制因子表达缺失的共同机制。我们之前证明，在未转化的肺上皮细胞系中，Wnt7a的缺失导致细胞生长增加，3-D培养生长改变，迁移增加。与匹配的正常肺组织相比，Wnt7a启动子在NSCLC肿瘤组织中具有更高的甲基化百分比，启动子区域的甲基化导致活性降低。我们用5-Aza-2 ' -脱氧胞苷处理H157和H1299 NSCLC细胞系，检测到Wnt7a启动子甲基化缺失，Wnt7a表达增加，Wnt7a肺信号通路活性增加。当DNMT1表达被shRNA敲除时，Wnt7a表达增加，甲基化减少。这些数据表明，在非小细胞肺癌中，Wnt7a在一部分肿瘤中因甲基化而丢失，而这种甲基化由DNMT1维持。通过去甲基化恢复Wnt7a的表达可能是治疗非小细胞肺癌的重要治疗方法。
Wnt7a is known to be a tumor suppressor that is lost in NSCLC, but no mechanism of loss has been established. Methylation of promoter regions has been established as a common mechanism of loss of tumor suppressor expression in NSCLC. We previously demonstrated that loss of Wnt7a in non-transformed lung epithelial cell lines led to increased cell growth, altered 3-D culture growth, and increased migration. The Wnt7a promoter has a higher percentage of methylation in NSCLC tumor tissue compared to matched normal lung tissue and methylation of the promoter region leads to decreased activity. We treated H157 and H1299 NSCLC cell lines with 5-Aza-2′-deoxycytidine and detected loss of Wnt7a promoter methylation, increased Wnt7a expression, and increased activity of the Wnt7a lung signaling pathway. When DNMT1 expression was knocked down by shRNA, expression of Wnt7a increased and methylation decreased. Together these data suggest that in NSCLC, Wnt7a is lost by methylation in a subset of tumors and that this methylation is maintained by DNMT1. Restoration of Wnt7a expression through demethylation could be an important therapeutic approach in the treatment of NSCLC.
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