title: Histone H3K27 Trimethylation Modulates 5-Fluorouracil Resistance by Inhibiting PU.1 Binding to the DPYD Promoter.
abstract: The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) is a major determinant of 5-FU response and toxicity. Although DPYD variants may affect 5-FU metabolism, they do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that H3K27 trimethylation (H3K27me3) at the DPYD promoter regulated by Ezh2 and UTX suppresses DPYD expression by inhibiting transcription factor PU.1 binding, leading to increased resistance to 5-FU. Enrichment of H3K27me3 at the DPYD promoter was negatively correlated with both DPYD expression and DPD enzyme activity in peripheral blood specimens from healthy volunteers. Lastly, tumor expression data suggest that DPYD repression by Ezh2 predicts poor survival in 5-FU-treated cancers. Collectively, the findings of the present article suggest that a previously uncharacterized mechanism regulates DPD expression and may contribute to tumor resistance to 5-FU. Cancer Res; 76(21); 6362-73. ©2016 AACR.
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.
authors: Rentian
authors: R
authors: Wu
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.
authors: Qian
authors: Q
authors: Nie
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.
authors: Erin E
authors: EE
authors: Tapper
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.
authors: Calvin R
authors: CR
authors: Jerde
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.
authors: Garrett S
authors: GS
authors: Dunlap
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.
authors: Shikshya
authors: S
authors: Shrestha
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.|Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota.
authors: Tarig A
authors: TA
authors: Elraiyah
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota. diasio.robert@mayo.edu offer.steven1@mayo.edu.|Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota.
authors: Steven M
authors: SM
authors: Offer
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota. diasio.robert@mayo.edu offer.steven1@mayo.edu.|Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota.
authors: Robert B
authors: RB
authors: Diasio
mesh_terms: D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000502:physiology; D005472:Fluorouracil / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D042943:Dihydrouracil Dehydrogenase (NADP); D000071221:Enhancer of Zeste Homolog 2 Protein; D005472:Fluorouracil; D006657:Histones; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C498409:EZH2 protein, human