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

Authors:
Michelle Vaz
Michelle Vaz
University of Illinois at Chicago
United States
Stephen Y Hwang
Stephen Y Hwang
The Sidney Kimmel Comprehensive Cancer Center
Baltimore | United States
Ioannis Kagiampakis
Ioannis Kagiampakis
College Station
United States
Jillian Phallen
Jillian Phallen
The Johns Hopkins University School of Medicine
United States
Ashwini Patil
Ashwini Patil
The University of Tokyo
Japan
Lauren Murphy
Lauren Murphy
Mayo Clinic
United States
Cynthia A Zahnow
Cynthia A Zahnow
Johns Hopkins University School of Medicine
United States

Cancer Cell 2017 09;32(3):360-376.e6

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

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.

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http://dx.doi.org/10.1016/j.ccell.2017.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596892PMC
September 2017
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