| Autor: |
Ting Zhang, Alisa Ambrodji, Huixing Huang, Kelly J Bouchonville, Amy S Etheridge, Remington E Schmidt, Brianna M Bembenek, Zoey B Temesgen, Zhiquan Wang, Federico Innocenti, Deborah Stroka, Robert B Diasio, Carlo R Largiadèr, Steven M Offer |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
eLife, Vol 13 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2050-084X |
| DOI: |
10.7554/eLife.94075 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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