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

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

Author information

1
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Krieger School of Arts and Sciences, Baltimore, MD 21218, USA.
3
Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.
4
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
5
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: heaswar2@jhmi.edu.
6
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu.

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

PMID:
28898697
PMCID:
PMC5596892
DOI:
10.1016/j.ccell.2017.08.006
[Indexed for MEDLINE]
Free PMC Article

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