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Molecular Pharmacology

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Research ArticleArticle

Transcriptional Regulation of Human CYP2A13 Expression in the Respiratory Tract by CCAAT/Enhancer Binding Protein and Epigenetic Modulation

Guoyu Ling, Yuan Wei and Xinxin Ding
Molecular Pharmacology March 2007, 71 (3) 807-816; DOI: https://doi.org/10.1124/mol.106.031104
Guoyu Ling
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Yuan Wei
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Xinxin Ding
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Abstract

CYP2A13, which is highly active in the metabolic activation of tobacco-specific nitrosamines, is selectively expressed in the respiratory tract, in which it is believed to play an important role in chemical carcinogenesis. The aim of this study was to determine the basis for tissue-specific regulation of CYP2A13 gene expression. We have shown that expression of CYP2A3, the rat homolog of CYP2A13, is regulated by nuclear factor I (NFI) in a tissue-specific manner. In the present study, we found that the transcriptional regulation of human CYP2A13 gene involves CCAAT/enhancer binding protein (C/EBP) transcription factors instead of NFI. DNase I footprinting and gel-shift assays with human lung nuclear extract identified two DNA elements bound by C/EBP. Reporter gene assays using a 216-base pair CYP2A13 promoter fragment confirmed the activation of CYP2A13 by transfected C/EBP factors, and results from chromatin immunoprecipitation assays indicated that C/EBP is associated with CYP2A13 promoter in vivo in the olfactory mucosa of CYP2A13-transgenic mice. In NCI-H441 human lung cancer cells, we discovered that CYP2A13 expression can be induced by a combined treatment with 5-aza-2′-deoxycytosine, a DNA demethylation agent, and trichostatin, a histone deacetylation inhibitor. In 5-aza-2′-deoxycytosine/trichostatin-treated NCI-H441 cells, overexpression of C/EBPδ, a lung-enriched C/EBP, led to additional increases in CYP2A13 expression, whereas C/EBPδ knockdown by small interference RNA suppressed CYP2A13 expression, findings that confirm a role for C/EBP in CYP2A13 regulation. Our findings pave the way for further studies of the regulation of the CYP2A13 gene, particularly the gene's potential suppression by airway inflammation, and the role of epigenetic modulation in the gene's tissue-selective expression.

Footnotes

  • This work was supported in part by United States Public Health Service grant CA092596 from the National Institutes of Health.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.031104.

  • ABBREVIATIONS: P450, cytochrome P450; ATCC, American Type Culture Collection; AzaC, 5-aza-2′-deoxycytosine; C/EBP, CCAAT/enhancer binding protein; ChIP, chromatin immunoprecipitation; HDAC, histone deacetylase; NFI, nuclear factor I; PCR, polymerase chain reaction; RACE, rapid amplification of cDNA ends; bZIP, basic region-leucine zipper; siRNA, small interference RNA; TBP, TATA box binding protein; TSA, trichostatin A; TSS, transcription start site; ANOVA, analysis of variance; HEK, human embryonic kidney; kb, kilobase(s); bp, base pair(s).

    • Received September 20, 2006.
    • Accepted December 5, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (3)
Molecular Pharmacology
Vol. 71, Issue 3
1 Mar 2007
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Research ArticleArticle

Transcriptional Regulation of Human CYP2A13 Expression in the Respiratory Tract by CCAAT/Enhancer Binding Protein and Epigenetic Modulation

Guoyu Ling, Yuan Wei and Xinxin Ding
Molecular Pharmacology March 1, 2007, 71 (3) 807-816; DOI: https://doi.org/10.1124/mol.106.031104

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Research ArticleArticle

Transcriptional Regulation of Human CYP2A13 Expression in the Respiratory Tract by CCAAT/Enhancer Binding Protein and Epigenetic Modulation

Guoyu Ling, Yuan Wei and Xinxin Ding
Molecular Pharmacology March 1, 2007, 71 (3) 807-816; DOI: https://doi.org/10.1124/mol.106.031104
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