Inactivation Of SMARCA2 By Promoter Hypermethylation Drives Lung Cancer Development

【Background】Malignant cancer is one type of diseases which forming a threat to human health.Lung cancer is one of the most common malignant tumors worldwide.According to the latest statistical data of International National Central Cancer Registry of China(NCCR),an estimated 73.3 million new lung cancer cases and 61.0 million deaths lung cancer deaths occured in China in 2015,with the most common incident cancer and the leading cause of cancer death.According to the differences of biological characteristics,clinical treatment,prognosis and the others,lung cancer can be categorized into two major types: non-small cell lung cancer(NSCLC)and small cell lung cancer(SCLC).NSCLC occupies more than 85% of all lung cancer cases,which is divided into adenocarcinoma(account for about 50%)and squamous cell carcinoma(account for about 40%).The occurrence of lung squamous cell carcinoma is the result of the combination of environmental factors(such as tobacco exposure)and genetic factors.Lung squamous cell carcinoma causes approximately 400,000 deaths per year worldwide and has become an urgent problem of public health.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.【Methods】 We applied multi-omics analysis to explored the mechanism of SMARCA2 inactivation in TCGA database.We performed the dCas9-DNMT3 a system to evaluate the role of promoter methylation in SMARCA2 transcriptional regulation.We assessed the tumor suppressing roles of SMARCA2 in lung cancer development by in vitro experiments.【Results】 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-DNMT3 a 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 [HR=0.35(0.27-0.45)].Besides,we found that SMARCA2 was a tumor suppressor and can significantly inhibit lung cancer cell vitality.【Conclusion】 we found that promoter hypermethylation contribute to the inactivation of SMARCA2.We also verified its oncogenetic roles of SMARCA2 inactivation in lung adenocarcinoma,which may provide a potential target for the clinical treatment.