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Research ArticleArticle

Reversible Epigenetic Regulation of 14-3-3σ Expression in Acquired Gemcitabine Resistance by Uhrf1 and DNA Methyltransferase 1

Li Qin, Zizheng Dong and Jian-Ting Zhang
Molecular Pharmacology November 2014, 86 (5) 561-569; DOI: https://doi.org/10.1124/mol.114.092544
Li Qin
Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana
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Zizheng Dong
Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana
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Jian-Ting Zhang
Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana
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Abstract

Although gemcitabine is the most commonly used drug for treating pancreatic cancers, acquired gemcitabine resistance in a substantial number of patients appears to hinder its effectiveness in successful treatment of this dreadful disease. To understand acquired gemcitabine resistance, we generated a gemcitabine-resistant pancreatic cancer cell line using stepwise selection and found that, in addition to the known mechanisms of upregulated expression of ribonucleotide reductase, 14-3-3σ expression is dramatically upregulated, and that 14-3-3σ overexpression contributes to the acquired resistance to gemcitabine and cross-resistance to cytarabine. We also found that the increased 14-3-3σ expression in the gemcitabine-resistant cells is due to demethylation of the 14-3-3σ gene during gemcitabine selection, which could be partially reversed with removal of the gemcitabine selection pressure. Most importantly, the reversible methylation/demethylation of the 14-3-3σ gene appears to be carried out by DNA methyltransferase 1 under regulation by Uhrf1. These findings suggest that the epigenetic regulation of gene expression may play an important role in gemcitabine resistance, and that epigenetic modification is reversible in response to gemcitabine treatment.

Footnotes

    • Received March 4, 2014.
    • Accepted September 4, 2014.
  • This work was supported in part by the National Institutes of Health [Grant R01-CA140582].

  • dx.doi.org/10.1124/mol.114.092544.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Research ArticleArticle

Regulation of 14-3-3σ Expression in Gemcitabine Resistance

Li Qin, Zizheng Dong and Jian-Ting Zhang
Molecular Pharmacology November 1, 2014, 86 (5) 561-569; DOI: https://doi.org/10.1124/mol.114.092544

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Research ArticleArticle

Regulation of 14-3-3σ Expression in Gemcitabine Resistance

Li Qin, Zizheng Dong and Jian-Ting Zhang
Molecular Pharmacology November 1, 2014, 86 (5) 561-569; DOI: https://doi.org/10.1124/mol.114.092544
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