Department of Cardio-Vascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 211166, China; Department of Cardiothoracic Surgery, The Third People's Hospital of Yancheng City, Yancheng 224000, China.
Department of Cardio-Vascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 211166, China.
Gene. 2019 Mar 1;687:193-199. doi: 10.1016/j.gene.2018.11.032. Epub 2018 Nov 14.
The SWI/SNF complex is a multimeric chromatin remodeling complex that has vital roles in regulating gene expression and cancer development. However, to date few studies have deeply explored the mechanism of SMARCA2 inactivation. We applied multi-omics analysis to explore the mechanism of SMARCA2 inactivation in The Cancer Genome Atlas (TCGA) database and performed the dCas9-DNMT3a system to evaluate the role of promoter methylation in SMARCA2 transcriptional regulation. We also assessed the tumor suppressing roles of SMARCA2 in lung cancer development by in vitro experiments. SMARCA2 promoter hypermethylation was significantly associated with decreased expression of SMARCA2. This result was further confirmed in the results of our own tissues. In addition, we observed that the mRNA level decreased by about 3 folds while the CpG island of promoter is nearly 30% hypermethylated by dCas9-DNMT3a system in H1299 cells. We identified SMARCA2 as a tumor suppressor gene whose expression was downregulated in lung cancers. Its inactivation was significantly associated with the poor survival of lung cancer patients [hazard ratio, HR = 0.35 (0.27-0.45)]. Besides, we found that SMARCA2 was a tumor suppressor and can significantly inhibit lung cancer cell vitality. We found that promoter hypermethylation contribute to the inactivation of SMARCA2. We also verified its oncogenetic roles of BRM inactivation in lung adenocarcinoma, which may provide a potential target for the clinical treatment.
SWI/SNF 复合物是一种多聚体染色质重塑复合物，在调节基因表达和癌症发展中起着至关重要的作用。然而，迄今为止，很少有研究深入探讨 SMARCA2 失活的机制。我们应用多组学分析方法来探索 TCGA 数据库中 SMARCA2 失活的机制，并使用 dCas9-DNMT3a 系统来评估启动子甲基化在 SMARCA2 转录调控中的作用。我们还通过体外实验评估了 SMARCA2 在肺癌发展中的肿瘤抑制作用。SMARCA2 启动子超甲基化与 SMARCA2 表达降低显著相关。这一结果在我们自己的组织结果中得到了进一步证实。此外，我们观察到在 H1299 细胞中，dCas9-DNMT3a 系统使启动子的 CpG 岛大约 30%超甲基化时，mRNA 水平降低了约 3 倍。我们确定 SMARCA2 是一种抑癌基因，其在肺癌中的表达下调。其失活与肺癌患者的不良预后显著相关[风险比，HR=0.35（0.27-0.45）]。此外，我们发现 SMARCA2 是一种肿瘤抑制因子，可显著抑制肺癌细胞活力。我们发现启动子超甲基化导致 SMARCA2 失活。我们还验证了 BRM 失活在肺腺癌中的致癌作用，这可能为临床治疗提供一个潜在的靶点。
