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Cigarette smoke induces demethylation of prometastatic oncogene synuclein-γ in lung cancer cells by downregulation of DNMT3B

Oncogene volume 26, pages 5900–5910 (2007)Cite this article

Abstract

The prometastatic oncogene synuclein-γ (SNCG) is not expressed in normal lung tissues, but it is highly expressed in lung tumors. Here, we show that cigarette smoke extract (CSE) has strong inducing effects on SNCG gene expression in A549 lung cancer cells through demethylation of SNCG CpG island. CSE treatment also augments the invasive capacity of A549 cells in an SNCG-dependent manner. To elucidate the mechanisms underlying the demethylating effects of CSE, we examined expression levels of DNA methyltransferases (DNMTs), 1, 3A and 3B in CSE-treated cells. We show that the mRNA expression of DNMT3B is specifically downregulated by CSE with a kinetics concurrent to SNCG reexpression. Utilizing siRNA to knockdown DNMT3B expression, we show that inhibition of DNMT3B directly increases SNCG mRNA expression. We further show that exogenous overexpression of DNMT3B in an SNCG-positive lung cancer cell line H292 suppresses SNCG mRNA and protein expression and induces de novo methylation of SNCG CpG island, whereas overexpression of DNMT1 or DNMT3A has no effects. Taken together, these new findings demonstrate that tobacco exposure induces the abnormal expression of SNCG in lung cancer cells through downregulation of DNMT3B. This work sheds light on the molecular understanding of demethylation of this oncogene during cancer progression.

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Acknowledgements

This study was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service) and by grants (BC010046 and BC033154) from the United States Army Medical Research and Material Command.

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Author notes

  1. H Liu and Y Zhou: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA, USA

    H Liu, Y Zhou & J Liu

  2. Lovelace Respiratory Research Institute, Albuquerque, NM, USA

    S E Boggs & S A Belinsky

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  1. H Liu
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  2. Y Zhou
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  3. S E Boggs
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  4. S A Belinsky
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  5. J Liu
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Correspondence to J Liu.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Liu, H., Zhou, Y., Boggs, S. et al. Cigarette smoke induces demethylation of prometastatic oncogene synuclein-γ in lung cancer cells by downregulation of DNMT3B. Oncogene 26, 5900–5910 (2007). https://doi.org/10.1038/sj.onc.1210400

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