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BRG1 loss is frequent in lung cancer and transforms lung epi-thelial cells via transcriptional and epigenetic reprograming

ABSTRACT: Background/Objectives: BRG1 loss-of-function (LOF) mutation is found in ~10% non-small cell lung cancer (NSCLC) but its role in lung tumorigenesis is unclear and investigated in this study. Methods: BRG1-knockout (KO) lines were generated from various non-malignant, pre-malignant, and malignant human lung epithelia-derived cell lines using CRISPR. Effects of BRG1-KO on cell growth, transcriptome, methylome, and epigenetic therapy were compared with wild-type (BRG1-WT) isogenic controls using standard in vitro and in vivo assays. Results: BRG1 protein was expressed in all non/pre-malignant lung epithelial cells but lost in 47% (14/30) of NSCLC cell lines. BRG1-KO and cigarette smoke (CS) exposure individually transformed human bronchial epithelial cell lines (HBECs) as evident by anchorage-independent growth. BRG1-KO and CS produced additive to synergistic effects on sensitivity to transformation that differed across HBECs. RNA-seq analysis revealed BRG1-KO significantly changed expression of over 8,500 genes on average impacting lung development, function, damage repair and cancer pathways including axonal guidance, pulmonary wound healing, and epithelial-to-mesenchymal transition (EMT). BRG1-KO also led to hypermethylation of >47,000 promoter CpGs within ~9,500 genes on average in different HBECs that included silencing of epithelial genes involved in EMT and tumor suppressor genes. BRG1-KO also moderately increased the in vitro and in vivo sensitivity of NSCLC cells to some epigenetic drugs. Conclusion: BRG1-LOF is frequent in NSCLC, can drive transformation of lung epithelial cells to acquire properties of premalignant cells indicating a potential role in lung cancer initiation, and sensitizes lung tumors to epigenetic therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307857 | GEO | 2025/11/14

REPOSITORIES: GEO

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BRG1 loss is frequent in lung cancer and transforms lung epi-thelial cells via transcriptional and epigenetic reprograming

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