Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States.
Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Elife. 2024 Apr 30;13:RP94075. doi: 10.7554/eLife.94075.
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, 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 that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls 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 promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
增强子对于调控组织特异性基因表达至关重要，而增强子区域内的遗传变异被认为与多种与癌症相关的过程有关，包括治疗抵抗。然而，确切的机制仍不清楚。使用一个明确的药物-基因对，我们鉴定出一个与抗癌药物 5-氟尿嘧啶（5-FU）代谢相关的二氢嘧啶脱氢酶（DPD，基因）表达的增强子区域。通过报告基因系统、CRISPR 基因组编辑细胞模型和人类肝脏标本，我们在体外和体内证明了位于这个新增强子内的常见种系变异（rs4294451；全球 27%的次要等位基因频率）的基因型状态控制着转录，并改变了对 5-FU 的耐药性。该变异基因型增加了转录因子 CEBPB 对增强子的募集，并改变了增强子和 启动子之间直接相互作用的水平。我们的数据为控制对 5-FU 的敏感性和耐药性的调控机制提供了深入了解。
