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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations.

Authors: Vaz, Michelle; Hwang, Stephen Y; Kagiampakis, Ioannis; Phallen, Jillian; Patil, Ashwini; O'Hagan, Heather M; Murphy, Lauren; Zahnow, Cynthia A; Gabrielson, Edward; Velculescu, Victor E; Easwaran, Hariharan P; Baylin, Stephen B

Published In Cancer Cell, (2017 Sep 11)

Abstract: We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.

PubMed ID: 28898697 Exiting the NIEHS site

MeSH Terms: Animals; Bronchi/pathology*; Carcinoma, Non-Small-Cell Lung/genetics; Carcinoma, Non-Small-Cell Lung/pathology; Cell Proliferation/genetics; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/pathology*; Chromatin/metabolism; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases/metabolism; DNA Damage; DNA Methylation/genetics; Enhancer of Zeste Homolog 2 Protein/metabolism; Epigenomics*; Epithelial Cells/metabolism*; Epithelial Cells/pathology; Epithelial-Mesenchymal Transition/genetics; Gene Expression Regulation, Neoplastic; Genome, Human; Humans; Lung Neoplasms/genetics; Lung Neoplasms/pathology; Male; Mice; Mutation/genetics*; Phenotype; Promoter Regions, Genetic/genetics; Proto-Oncogene Proteins p21(ras)/genetics*; Signal Transduction/genetics; Sirtuin 1/metabolism; Smoking/adverse effects*; Smoking/genetics*

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