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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 vari...

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyses the conversion of prostaglandin E

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of prostaglandin E2 (PGE2) to a biologically inactive keto metabolite 15-keto-PGE2. However, the molecular mechanisms underlying regulation of 15-PGDH expression remain largely elusive. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been reported to have anti-inflammatory and anti-carcinogenic activities. In the present study, we have found that 15-PGJ2 upregulates expression and catalytic activity of 15-PGDH in human breast cancer (MDA-MB-231) cells. 15d-PGJ2 treatment decreased the CpG methylation in the 15-PGDH promoter in MDA-MB-231 cells as determined by the bisulfite genome sequencing and methyl-specific PCR. 15d-PGJ2 inhibited catalytic activity of methyltransferase 1 (DNMT1) but did not influence DNMT expression. 15d-PGJ2 increased the expression of c-Fos which is a functional subunit of AP-1. Chromatin-immunoprecipitation analysis revealed that 15d-PGJ2 significantly attenuated DNMT1 binding to the site for AP-1 transcription factor present in the 15-PGDH promoter regions, while increasing c-Fos binding. Biotin-tagged 15d-PGJ2 directly bound to DNMT1, and reduced its catalytic activity. A non-electrophilic 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. This findings suggests that the α,β-unsaturated carbonyl group of 15d-PGJ2 is essential for its inactivation of DNMT1 and expression of 15-PGDH. In conclusion, 15d-PGJ2 directly interacts with DNMT1 and consequently suppresses DNMT1-mediated hypermethylation of 15-PGDH promoter, leading to upregulation of 15-PGDH expression. Citation Format: Hye-Ok Jang, Hye-Rim Kim Kim, Ha-Na Lee, Do-Hee Kim, Young-Joon Surh, Hye-Kyung Na. Upregulation of 15-hydroxyprostaglandin dehydrogenase expression by 15-Deoxy-Δ12,14-prostaglandin J2 through inactivation of DNA methyltransferase 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 273.

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the conversion of prostaglandin E2 to a biologically inactive keto metabolite. The down regulation of 15-PGDH is ubiquitously observed in various human malignancies including breast cancer. Hypermethylation of CpG islands present in the gene promoter region is considered to silence the expression of 15-PGDH. However, the molecular mechanisms underlying regulation of 15-PGDH remain largely unknown. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been reported to have anti-inflammatory and anti-carcinogenic activities. In the present study, we have found that 15-PGJ2 upregulates 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 bisulfite genome sequencing and methyl specific PCR. 15d-PGJ2 inhibited catalytic activity of methyltransferase 1 (DNMT1) but did not influence expression of either mRNA or protein of DNMT1. siRNA knockdown of DNMT1 induced expression of 15-PGDH. 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 site for AP-1 transcription factor present in the 15-PGDH promoter regions. We also observed that 15-PGJ2 induced expression of c-Fos, but not c-Jun in the nuclear extract of MDA-MD-231 cells. Moreover, 15d-PGJ2 increased the c-Fos binding to the 15-PGDH promoter regions. A non-electrophilic analogue 9,10-dihydro-15d-PGJ2 failed to suppress the methylation of CpG islands present in 15-PGDH promoter and did not affect DNMT1 activity and 15-PGDH expression. This finding suggests that the α,β-unsaturated carbonyl group is essential for 15d-PGJ2-mediated inactivation of DNMT1 and expression of 15-PGDH. In conclusion, 15d-PGJ2 plays as a hypomethylating agent through direct interaction with DNMT1 and thereby suppresses DNMT1-mediated hypermethylation of 15-PGDH promoter, leading to upregulation of 15-PGDH expression. Citation Format: Hye-Ok Jang, Ha-Na Lee, Areumnuri Kim, Do-Hee Kim, Young-Joon Surh, Hye-Kyung Na. 15-Deoxy-Δ12,14-prostaglandin J2 upregulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltrasferase 1 inactivation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2297. doi:10.1158/1538-7445.AM2014-2297