Abstract
<div>Abstract<p>The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) is a major determinant of 5-FU response and toxicity. Although <i>DPYD</i> variants may affect 5-FU metabolism, they do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that H3K27 trimethylation (H3K27me3) at the <i>DPYD</i> promoter regulated by Ezh2 and UTX suppresses <i>DPYD</i> expression by inhibiting transcription factor PU.1 binding, leading to increased resistance to 5-FU. Enrichment of H3K27me3 at the <i>DPYD</i> promoter was negatively correlated with both <i>DPYD</i> expression and DPD enzyme activity in peripheral blood specimens from healthy volunteers. Lastly, tumor expression data suggest that <i>DPYD</i> repression by Ezh2 predicts poor survival in 5-FU–treated cancers. Collectively, the findings of the present article suggest that a previously uncharacterized mechanism regulates DPD expression and may contribute to tumor resistance to 5-FU. <i>Cancer Res; 76(21); 6362–73. ©2016 AACR</i>.</p></div>
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