Abstract
Malignant lung cancer cells are characterized by uncontrolled proliferation and migration. Aberrant lung cancer cell proliferation and migration are programmed by altered cancer transcriptome. The underlying epigenetic mechanism is unclear. Here we report that expression levels of BRG1, a chromatin remodeling protein, were significantly up-regulated in human lung cancer biopsy specimens of higher malignancy grades compared to those of lower grades. Small interfering RNA mediated depletion or pharmaceutical inhibition of BRG1 suppressed proliferation and migration of lung cancer cells. BRG1 depletion or inhibition was paralleled by down-regulation of cyclin B1 (CCNB1) and latent TGF-β binding protein 2 (LTBP2) in lung cancer cells. Further analysis revealed that BRG1 directly bound to the CCNB1 promoter to activate transcription in response to hypoxia stimulation by interacting with E2F1. On the other hand, BRG1 interacted with Sp1 to activate LTBP2 transcription. Mechanistically, BRG1 regulated CCNB1 and LTBP2 transcription by altering histone modifications on target promoters. Specifically, BRG1 recruited KDM3A, a histone H3K9 demethylase, to remove dimethyl H3K9 from target gene promoters thereby activating transcription. KDM3A knockdown achieved equivalent effects as BRG1 silencing by diminishing lung cancer proliferation and migration. Of interest, BRG1 directly activated KDM3A transcription by forming a complex with HIF-1α. In conclusion, our data unveil a novel epigenetic mechanism whereby malignant lung cancer cells acquired heightened ability to proliferate and migrate. Targeting BRG1 may yield effective interventional strategies against malignant lung cancers.
Highlights
Lung cancer represents one of the most deadly cancers in both industrialized and developing countries[1,2]
We report that Brahma related gene 1 (BRG1) contributes to hypoxia-induced transcription of genes involved in cancer cell proliferation and migration by interacting with different sequence-specific transcription factors
Elevated BRG1 expression correlates with augmented lung cancer malignancy in humans We first examined the expression levels of BRG1 in a small cohort of lung cancer biopsy specimens
Summary
Lung cancer represents one of the most deadly cancers in both industrialized and developing countries[1,2]. Normal epithelial cells acquire the ability of aggressive proliferation and migration contributing to tumor growth and dissemination[3]. Aberrant cancer cell proliferation and migration are regulated by a. Li et al Oncogenesis (2019)8:66 promote proliferation and migration is not completely understood. Brahma related gene 1 (BRG1) is the catalytic component of the mammalian SWI/SNF chromatin remodeling complex intimately involved in transcriptional regulation[6]. BRG1 characteristically functions within the confines of a multifactor epigenetic complex that include other subunits of the SWI/SNF proteins (e.g., BRG1associated factors or BAFs) but histone/DNA modifying enzymes and non-coding regulatory RNAs7. The compositions of the BRG1-containing complexes appear to be rather flexible so that BRG1 regulates transcription in a cell type and context-dependent manner. Postnatal activation of BRG1, has been found to be associated with a host of human diseases including atherosclerosis[9], pulmonary hypertension[10], pathological hypertrophy[11], alcoholic steatohepatitis[12,13], and abdominal aortic aneurysm[14]
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