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Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD).
Zhang, Ting; Ambrodji, Alisa; Huang, Huixing; Bouchonville, Kelly J; Etheridge, Amy S; Schmidt, Remington E; Bembenek, Brianna M; Temesgen, Zoey B; Wang, Zhiquan; Innocenti, Federico; Stroka, Deborah; Diasio, Robert B; Largiadèr, Carlo R; Offer, Steven M.
  • Zhang T; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States.
  • Ambrodji A; Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Huang H; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
  • Bouchonville KJ; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States.
  • Etheridge AS; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States.
  • Schmidt RE; Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, United States.
  • Bembenek BM; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States.
  • Temesgen ZB; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States.
  • Wang Z; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States.
  • Innocenti F; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, United States.
  • Stroka D; Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, United States.
  • Diasio RB; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Largiadèr CR; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States.
  • Offer SM; Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Elife ; 132024 Apr 30.
Article en En | MEDLINE | ID: mdl-38686795
ABSTRACT
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Elementos de Facilitación Genéticos / Dihidrouracilo Deshidrogenasa (NADP) / Epigénesis Genética / Fluorouracilo Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Elementos de Facilitación Genéticos / Dihidrouracilo Deshidrogenasa (NADP) / Epigénesis Genética / Fluorouracilo Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article