Epigenetic silencing of genes and microRNAs (miRs) via chromatin remodeling and cytosine methylation has emerged as a major mechanism in lung cancer etiology. The reversal of gene and miR silencing using pharmacological agents by affecting cytosine-DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), or histone deacetylases (HDACs) offers new strategies for prevention and intervention for lung cancer. We have developed an in vitro model using hTERT/cdk4 immortalized human bronchial epithelial cell lines (HBECs) that identifies molecular changes driving transformation of preneoplastic lung epithelial cells during exposure to carcinogens found in mainstream and environmental tobacco smoke. Our studies provided a mechanistic link between increased DNMT1 protein, de novo methylation of genes, and reduced DNA repair capacity that together seemed causal for transformation. Our recent studies show that the exposure of HBECs to carcinogens for 4 wk induces a persistent and irreversible, multifaceted dedifferentiation program characterized by the epithelial-to-mesenchymal transition (EMT). EMT induction was epigenetically driven, initially by chromatin remodeling involving H3K27me3 enrichment, with ensuing DNA methylation sustaining the silencing of miR-200b, -200c, and -205 implicated in this developmental program and persisting in malignant tumors. Over expression of these miRs reversed transformation. Next generation sequencing of transformed HBEC lines has identified 25 miRs whose silencing may be regulated through chromatin remodeling and promoter methylation. The impact of specific miRs identified by sequencing on transformation, regulation by chromatin, and their prevalence in lung cancer will be described. (Supported by R01 ES008801 and P50 CA58184).
Citation Format: Steven A. Belinsky, Avrum Spira, Carmen Tellez. Epigenetic deregulation of microRNAs during tobacco carcinogen-induced transformation of bronchial epithelial cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN06-02.