Histone H3K27 trimethylation modulates 5-fluorouracil resistance by inhibiting PU.1 binding to the DPYD promoter

Rentian Wu, Qian Nie, Erin E. Tapper, Calvin R. Jerde, Garrett S. Dunlap, Shikshya Shrestha, Tarig A. Elraiyah, Steven M. Offer, Robert B. Diasio

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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 DPYD 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 DPYD promoter regulated by Ezh2 and UTX suppresses DPYD expression by inhibiting transcription factor PU.1 binding, leading to increased resistance to 5-FU. Enrichment of H3K27me3 at the DPYD promoter was negatively correlated with both DPYD expression and DPD enzyme activity in peripheral blood specimens from healthy volunteers. Lastly, tumor expression data suggest that DPYD 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.

Original languageEnglish (US)
Pages (from-to)6362-6373
Number of pages12
JournalCancer research
Volume76
Issue number21
DOIs
StatePublished - Nov 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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