title: Reversible epigenetic regulation of 14-3-3σ expression in acquired gemcitabine resistance by uhrf1 and DNA methyltransferase 1.
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.
authors.affiliation: Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana jianzhan@iu.edu.
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D004247:DNA / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D010190:Pancreatic Neoplasms / Q000235:genetics; D012264:Ribonucleotide Reductases / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D048948:14-3-3 Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D003561:Cytarabine; D003841:Deoxycytidine; D004247:DNA; D012264:Ribonucleotide Reductases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; D000093542:Gemcitabine