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

doi:10.1158/0008-5472.CAN-16-1306

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

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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 and Robert B. Diasio

Cancer research (Chicago, Ill.), Vol.76(21), pp.6362-6373

11/01/2016

DOI: 10.1158/0008-5472.CAN-16-1306

PMCID: PMC5093042

PMID: 27578004

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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. While 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 tri-methylation (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 suggests that DPYD repression by Ezh2 predicts poor survival in 5-FU-treated cancers. Collectively, the findings of the present manuscript suggest that a previously uncharacterized mechanism regulates DPD expression and may contribute to tumor resistance to 5-FU.

Details

Title: Subtitle: Histone H3K27 trimethylation modulates 5-fluorouracil resistance by inhibiting PU.1 binding to the DPYD promoter
Creators: Rentian Wu - Mayo Clinic
Qian Nie - Mayo Clinic
Erin E. Tapper - Mayo Clinic
Calvin R. Jerde - Mayo Clinic
Garrett S. Dunlap - Mayo Clinic
Shikshya Shrestha - Mayo Clinic
Tarig A. Elraiyah - Mayo Clinic
Steven M. Offer - Mayo Clinic
Robert B. Diasio - Mayo Clinic
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.76(21), pp.6362-6373
DOI: 10.1158/0008-5472.CAN-16-1306
PMID: 27578004
PMCID: PMC5093042
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: DOI: 10.13039/100000002, name: NIH, award: NIH5P30CA015083-42
Language: English
Date published: 11/01/2016
Academic Unit: Pathology
Record Identifier: 9984618637502771

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