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Free Radic Res. 2019 Mar;53(3):335-347. doi: 10.1080/10715762.2019.1576867. Epub 2019 Mar 1.

15-Deoxy-Δ12,14-prostaglandin J2 up-regulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltransferase 1 inactivation.

Author information

1
a Department of Molecular Medicine and Biopharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul , South Korea.
2
b Tumor Microenvironment Global Core Research Center, College of Pharmacy , Seoul National University , Seoul , South Korea.
3
c Department of Food and Nutrition, College of Health & Wellness , Sungshin Women's University , Seoul , South Korea.
4
d Laboratory of Radiation Exposure & Therapeutics , National Radiation Emergency Medical Center , Seoul , South Korea.
5
e KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences , Seoul , South Korea.
6
f Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering , Sungshin Women's University , Seoul , South Korea.

Abstract

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyses the conversion of prostaglandin E2 to a keto metabolite. The expression of 15-PGDH is ubiquitously repressed in various human malignancies. However, the molecular mechanisms underlying down-regulation of 15-PGDH expression remain largely unknown. 15-Deoxy-△12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been reported to have anti-inflammatory and anticarcinogenic activities. In the present study, we have found that 15d-PGJ2 induces expression and catalytic activity of 15-PGDH in human breast cancer (MDA-MB-231) cells. 15d-PGJ2 decreased the level of CpG methylation in the 15-PGDH promoter in MDA-MB-231 cells as determined by the bisulphite genome sequencing and methyl-specific PCR. 15d-PGJ2 inhibited the catalytic activity of methyltransferase 1 (DNMT1) but did not influence its expression. Biotinylated 15d-PGJ2 directly interacted with DNMT1 and reduced its catalytic activity. Chromatin-immunoprecipitation analysis revealed that 15d-PGJ2 significantly attenuated DNMT1 binding to the activator protein-1 transcription factor present in the 15-PGDH promoter region. A nonelectrophilic analogue 9,10-dihydro-15d-PGJ2 failed to suppress the methylation of CpG islands present in 15-PGDH promoter and did not affect both DNMT1 activity and 15-PGDH expression. These findings suggest that the α,β-unsaturated carbonyl group present in 15d-PGJ2 is essential for its inactivation on DNMT1 and expression of 15-PGDH. In conclusion, 15d-PGJ2 plays as a hypomethylating agent through direct interaction with DNMT1 and consequently suppresses DNMT1-mediated hypermethylation of 15-PGDH promoter, leading to up-regulation of 15-PGDH expression.

KEYWORDS:

15-PGDH; 15d-PGJ; DNMT1; breast cancer; methylation

PMID:
30717608
DOI:
10.1080/10715762.2019.1576867
[Indexed for MEDLINE]

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