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15-Deoxy-Δ 12,14 -prostaglandin J 2 up-regulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltransferase 1 inactivation.
- Source :
-
Free radical research [Free Radic Res] 2019 Mar; Vol. 53 (3), pp. 335-347. Date of Electronic Publication: 2019 Mar 01. - Publication Year :
- 2019
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Abstract
- 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyses the conversion of prostaglandin E <subscript>2</subscript> 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-△ <superscript>12,14</superscript> -prostaglandin J <subscript>2</subscript> (15d-PGJ <subscript>2</subscript> ), 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-PGJ <subscript>2</subscript> induces expression and catalytic activity of 15-PGDH in human breast cancer (MDA-MB-231) cells. 15d-PGJ <subscript>2</subscript> 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-PGJ <subscript>2</subscript> inhibited the catalytic activity of methyltransferase 1 (DNMT1) but did not influence its expression. Biotinylated 15d-PGJ <subscript>2</subscript> directly interacted with DNMT1 and reduced its catalytic activity. Chromatin-immunoprecipitation analysis revealed that 15d-PGJ <subscript>2</subscript> 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-PGJ <subscript>2</subscript> 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-PGJ <subscript>2</subscript> is essential for its inactivation on DNMT1 and expression of 15-PGDH. In conclusion, 15d-PGJ <subscript>2</subscript> 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.
Details
- Language :
- English
- ISSN :
- 1029-2470
- Volume :
- 53
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Free radical research
- Publication Type :
- Academic Journal
- Accession number :
- 30717608
- Full Text :
- https://doi.org/10.1080/10715762.2019.1576867