Tobacco smoke induces polyeomb-mediated repression of Dickkopf-1 in lung cancer cells

Mustafa Hussain, Mahadev Rao, Ashley E. Humphries, Julie A. Hong, Fang Liu, Maocheng Yang, Diana Caragacianu, David S. Sehrump

Research output: Contribution to journalArticle

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Abstract

Limited information is available about epigenetic mechanisms by which cigarette smoke enhances the initiation and progression of lung cancer. To examine this issue, A549 and Calu-6 lung cancer cells were cultured in normal media with or without tobacco smoke condensate (TSC) under clinically relevant exposure conditions. Ten-day TSC exposure dramatically increased the tumorigenicity of lung cancer cells in nude mice. Microarray and quantitative reverse transcription-PCR (RT-PCR) experiments revealed that this phenomenon coincided with diminished expression of Dickkopf-1 (Dkk-1). Western blot, chromatin immunoprecipitation, methylation-specific PCR, and pyrosequencing experiments showed that repression of Dkk-1 coincided with decreased H4K16Ac, increased H3K27me3, and recruitment of SirTl, EZH2, SUZ12, and Bmil without DNA hypermethylation within the Dkk-1 promoter despite prolonged TSC exposures. Removal of TSC from culture media resulted in loss of promoter-associated polycomb repressor complexes and reexpression of Dkk-1. siRNA-mediated knockdown of EZH2 and SirT1 partially abrogated TSC-mediated inhibition of Dkk-1 expression. Western blot and quantitative RT-PCR array experiments showed that TSC exposure as well as knockdown of Dkk-1 activated Wnt signaling and significantly up-regulated Wnt5a in lung cancer cells. Knockdown of Dkk-1 recapitulated the dramatic protumorigenic effects of TSC exposure in Calu-6 cells. Despite the transient nature of Dkk-1 repression following TSC exposure in vitro, Dkk-1 remained silenced in tumor xenografts derived from TSC-treated Calu-6 cells. Collectively, these data provide evidence that cigarette smoke directly engages polycomb machinery to activate a signaling network implicated in maintenance of cancer stem cells.

Original languageEnglish
Pages (from-to)3570-3578
Number of pages9
JournalCancer Research
Volume69
Issue number8
DOIs
Publication statusPublished - 15-04-2009

Fingerprint

Smoke
Tobacco
Lung Neoplasms
Tobacco Products
Polymerase Chain Reaction
Reverse Transcription
Western Blotting
Neoplastic Stem Cells
Chromatin Immunoprecipitation
Heterografts
Epigenomics
Nude Mice
Methylation
Small Interfering RNA
Culture Media
Cultured Cells
Maintenance
DNA

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Hussain, M., Rao, M., Humphries, A. E., Hong, J. A., Liu, F., Yang, M., ... Sehrump, D. S. (2009). Tobacco smoke induces polyeomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Research, 69(8), 3570-3578. https://doi.org/10.1158/0008-5472.CAN-08-2807
Hussain, Mustafa ; Rao, Mahadev ; Humphries, Ashley E. ; Hong, Julie A. ; Liu, Fang ; Yang, Maocheng ; Caragacianu, Diana ; Sehrump, David S. / Tobacco smoke induces polyeomb-mediated repression of Dickkopf-1 in lung cancer cells. In: Cancer Research. 2009 ; Vol. 69, No. 8. pp. 3570-3578.
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Hussain, M, Rao, M, Humphries, AE, Hong, JA, Liu, F, Yang, M, Caragacianu, D & Sehrump, DS 2009, 'Tobacco smoke induces polyeomb-mediated repression of Dickkopf-1 in lung cancer cells', Cancer Research, vol. 69, no. 8, pp. 3570-3578. https://doi.org/10.1158/0008-5472.CAN-08-2807

Tobacco smoke induces polyeomb-mediated repression of Dickkopf-1 in lung cancer cells. / Hussain, Mustafa; Rao, Mahadev; Humphries, Ashley E.; Hong, Julie A.; Liu, Fang; Yang, Maocheng; Caragacianu, Diana; Sehrump, David S.

In: Cancer Research, Vol. 69, No. 8, 15.04.2009, p. 3570-3578.

Research output: Contribution to journalArticle

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