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

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

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57 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)360-376.e6
JournalCancer Cell
Volume32
Issue number3
DOIs
StatePublished - Sep 11 2017

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Keywords

  • DNA methylation
  • HBECs
  • Kras
  • addiction
  • cigarette smoke exposure
  • epigenetic
  • genetic
  • human bronchial epithelial cells
  • lung cancer
  • oncogene
  • polycomb

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Vaz, M., Hwang, S. Y., Kagiampakis, I., Phallen, J., Patil, A., O'Hagan, H. M., Murphy, L., Zahnow, C. A., Gabrielson, E., Velculescu, V. E., Easwaran, H. P., & 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