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Inactivation of SMARCA2 by promoter hypermethylation drives lung cancer development
- Wu, Jixiang, He, Keshuai, Zhang, Yajun, Song, Jixiang, Shi, Zhan, Chen, Weiwei, Shao, Yongfeng
- Gene 2019 v.687 pp. 193-199
- adenocarcinoma, carcinogenesis, chromatin, databases, gene expression, gene expression regulation, genomic islands, in vitro studies, lung neoplasms, lungs, messenger RNA, methylation, neoplasm cells, patients, tissues, transcription (genetics), tumor suppressor genes
- 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.