The study identified a novel cis enhancer region (E9) located approximately 9 kb upstream of the DPYD gene that regulates its expression. Using reporter assays, CRISPR genome editing, and human liver samples, the authors demonstrated that the genotype status of the common germline variant rs4294451 within the E9 enhancer controls DPYD transcription and alters cellular sensitivity to the anti-cancer drug 5-fluorouracil (5-FU).
The variant genotype (A allele) was associated with reduced recruitment of the transcription factor CEBPB to the E9 enhancer, decreased interactions between the enhancer and DPYD promoter, and lower DPYD expression. Cells carrying the A allele showed increased sensitivity to 5-FU compared to those with the reference T allele.
The authors provide mechanistic insights into how a regulatory genetic variant can impact drug metabolism and sensitivity, offering a potential biomarker for predicting 5-FU toxicity risk and resistance. The findings suggest that the rs4294451 variant, which is more common in individuals of African ancestry, could contribute to racial disparities in colorectal cancer outcomes with 5-FU-based therapies.
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by Zhang,T., Am... alle www.biorxiv.org 11-05-2023
https://www.biorxiv.org/content/10.1101/2023.11.01.565230v2Domande più approfondite