UV radiation inhibits 15-hydroxyprostaglandin dehydrogenase levels in human skin: evidence of transcriptional suppression.
Elevated levels of prostaglandins (PG) have been detected in the skin following UV radiation (UVR). PGs play an important role in mediating both the acute and the chronic consequences of UVR exposure. UVR-mediated induction of cyclooxygenase-2 (COX-2) contributes to increased PG synthesis. In theory, reduced catabolism might also contribute to increased PG levels. 15-Hydroxyprostaglandin deyhdrogenase (15-PGDH), a tumor suppressor gene, plays a major role in PG catabolism. In this study, we investigated whether UVR exposure suppressed 15-PGDH while inducing COX-2 in keratinocytes and in human skin. UVR exposure caused dose-dependent induction of COX-2, suppression of 15-PGDH, and increased prostaglandin E(2) (PGE(2)) production in HaCaT cells. Exposure to UVR suppressed the transcription of 15-PGDH, resulting in reduced 15-PGDH mRNA, protein, and enzyme activities. UVR exposure induced Slug, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Slug blocked UVR-mediated downregulation of 15-PGDH. The effects of UVR were also evaluated in the EpiDerm skin model, a three-dimensional model of human epidermis. Here too, COX-2 levels were induced and 15-PGDH levels suppressed following UVR exposure. Next, the effects of UVR were evaluated in human subjects. UVR treatment induced COX-2 while suppressing 15-PGDH mRNA in the skin of 9 of 10 subjects. Collectively, these data suggest that reduced expression of 15-PGDH contributes to the elevated levels of PGs found in the skin following UVR exposure. Possibly, agents that prevent UVR-mediated downregulation of 15-PGDH will affect the acute or the long-term consequences of UVR exposure, including nonmelanoma skin cancer.
Judson
Benjamin L
BL
Department of Medicine and Weill Cornell Cancer Center, 525 East 68th Street, Room F-206, New York, NY 10065, USA.
Miyaki
Akira
A
Kekatpure
Vikram D
VD
Du
Baoheng
B
Gilleaudeau
Patricia
P
Sullivan-Whalen
Mary
M
Mohebati
Arash
A
Nair
Sudhir
S
Boyle
Jay O
JO
Granstein
Richard D
RD
Subbaramaiah
Kotha
K
Krueger
James G
JG
Dannenberg
Andrew J
AJ
D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D011453:Prostaglandins / Q000378:metabolism; D011827:Radiation; D012867:Skin / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects*; D014158:Transcription, Genetic / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects*
D011453:Prostaglandins; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human