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

Cancer Cell. 2017 Sep 11;32(3):360-376.e6. doi: 10.1016/j.ccell.2017.08.006.

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.

Keywords: DNA methylation; HBECs; Kras; addiction; cigarette smoke exposure; epigenetic; genetic; human bronchial epithelial cells; lung cancer; oncogene; polycomb.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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*

Substances

  • Chromatin
  • KRAS protein, human
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Sirtuin 1
  • Proto-Oncogene Proteins p21(ras)