15-Deoxy-Δ^12,14-prostaglandin J₂ up-regulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltransferase 1 inactivation

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:

• 15d-PGJ₂
• 15-PGDH
• breast cancer
• DNMT1
• methylation

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Sungshin Women’s University Research Grant [2014-1-21-003].