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Original Research: COPD |

Cigarette Smoke-Induced Hypermethylation of the GCLC Gene Is Associated With COPD

Linling Cheng, MD, PhD; Jun Liu, MD; Bing Li, PhD; Shengming Liu, MD, PhD; Xianyan Li, MD; Hongbin Tu, PhD
Author and Funding Information

Dr Tu is currently at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Bethesda, MD).

FUNDING/SUPPORT: This study was supported by grants from the National Natural Science Foundation of China [30800498] and Guangdong Natural Science Foundation [S2013010016665]

CORRESPONDENCE TO: Hongbin Tu, PhD, NIH 10/4D57, MSC-1372, 9000 Rockville Pike, Bethesda, MD 20892


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(2):474-482. doi:10.1378/chest.14-2309
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Background  Cigarette smoking is a major environmental contributor to COPD, but understanding its epigenetic regulation of oxidative genes involved in the pathogenesis of COPD remains elusive.

Methods  We analyzed DNA methylation on glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase M1 (GSTM1), glutathione S-transferase P1 (GSTP1), and superoxide dismutase 3 (SOD3) promoters in clinical samples from patients with COPD (current-smoker [CS-COPD]; ex-smoker [ES-COPD]) and subjects with normal pulmonary function (current-smoker [CS-NS]; ex-smoker [ES-NS]; never-smoker [NC]). Expression of GCLC messenger RNA (mRNA) and glutathione (GSH) synthesis in these clinical samples and human bronchial epithelial (BEAS-2B) cells stimulated by cigarette-smoke extract (CSE) was evaluated. GCLC mRNA and protein levels were measured to determine effects of demethylation and deacetylation agents on CSE-treated BEAS-2B cells.

Results  The DNA methylation level of the GCLC promoter was significantly increased in CS-COPD, CS-NS, and ES-COPD groups compared with ES-NS and NC groups. However, there were no significant differences in DNA methylation values of GSTM1, GSTP1, and SOD3 promoters among these groups. Expression of GCLC mRNA was downregulated in the lungs, and GSH levels decreased in plasma as a consequence of hypermethylation of the GCLC promoter. Similarly, CSE-treated BEAS-2B cells had hypermethylation of the GCLC gene, mRNA downregulation, and a decreased intracellular GSH level. GCLC expression in CSE-treated BEAS-2B cells was restored by the methylation inhibitor, 5-aza-2ʹ-deoxycytidine, but not by the deacetylation agent, trichostatin A.

Conclusions  Cigarette smoke-induced hypermethylation of the GCLC promoter is related to the initiation and progression of COPD. Our finding may provide a new strategy for COPD intervention by developing demethylation agents targeting GCLC hypermethylation.

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