Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)

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

doi:10.7554/eLife.94075

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Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)

Journal article

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Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)

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, …

eLife, Vol.13, RP94075

04/30/2024

DOI: 10.7554/eLife.94075

PMCID: PMC11060711

PMID: 38686795

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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.

Cancer Biology

Genetics and Genomics

Details

Title: Subtitle: Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)
Creators: Ting Zhang - Mayo Clinic in Arizona
Alisa Ambrodji - University Hospital of Bern
Huixing Huang - Mayo Clinic
Kelly J Bouchonville - Mayo Clinic in Arizona
Amy S Etheridge - University of North Carolina at Chapel Hill
Remington E Schmidt - Mayo Clinic in Arizona
Brianna M Bembenek - Mayo Clinic in Arizona
Zoey B Temesgen - Mayo Clinic in Arizona
Zhiquan Wang - Mayo Clinic in Arizona
Federico Innocenti - University of North Carolina at Chapel Hill
Deborah Stroka - University of Bern
Robert B Diasio - Mayo Clinic in Arizona
Carlo R Largiadèr - University Hospital of Bern
Steven M Offer - University of Iowa
Resource Type: Journal article
Publication Details: eLife, Vol.13, RP94075
Publisher: eLife Sciences Publications, Ltd
DOI: 10.7554/eLife.94075
PMID: 38686795
PMCID: PMC11060711
ISSN: 2050-084X
eISSN: 2050-084X
Grant note: R01CA251065 / ; 320030_212583 / ;
Language: English
Date published: 04/30/2024
Academic Unit: Pathology
Record Identifier: 9984621360002771

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