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

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. [Display omitted] •Chronic smoke exposure causes sequential chromatin changes leading to gene silencing•Silenced genes are normally polycomb controlled but adopt abnormal DNA methylation•Gene methylation causes sequential upregulation of key signal transduction pathways•Epigenetic alterations sensitize cells to transformation by a single oncogenic event Vaz et al. show that long-term exposure of untransformed human bronchial epithelial cells to cigarette smoke condensate induces epigenetic changes, consistent with those commonly seen in smoking-related non-small cell lung cancer, that sensitize the cells to transformation with a single KRAS mutation.