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. 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.
CITATION STYLE
Vaz, M., Hwang, S. Y., Kagiampakis, I., Phallen, J., Patil, A., O’Hagan, H. M., … Baylin, S. B. (2017). Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell, 32(3), 360-376.e6. https://doi.org/10.1016/j.ccell.2017.08.006
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