Abstract
Ultraviolet (UV)-irradiated keratinocytes secrete the lipid mediator of inflammation, platelet-activating factor (PAF). PAF plays an essential role in UV-induced immune suppression and skin cancer induction. Dermal mast cell migration from the skin to the draining lymph nodes plays a prominent role in activating systemic immune suppression. UV-induced PAF activates mast cell migration by up-regulating mast cell CXCR4 surface expression. Recent findings indicate that PAF up-regulates CXCR4 expression via histone acetylation. UV-induced PAF also activates cell cycle arrest and disrupts DNA repair, in part by increasing p21 expression. Do epigenetic alterations play a role in p21 up-regulation? Here we show that PAF increases Acetyl-CREB-binding protein (CBP/p300) histone acetyltransferase expression in a time and dose-dependent fashion. Partial deletion of the HAT domain in the CBP gene, blocked these effects. Chromatin immunoprecipitation assays indicated that PAF-treatment activated the acetylation of the p21 promoter. PAF-treatment had no effect on other acetylating enzymes (GCN5L2, PCAF) indicating it is not a global activator of histone acetylation. This study provides further evidence that PAF activates epigenetic mechanisms to affect important cellular processes, and we suggest this bioactive lipid can serve as a link between the environment and the epigenome.
Highlights
The ultraviolet (UV) radiation in sunlight is the principal cause of both melanoma and non-melanoma skin cancer
We demonstrated that carbamyl PAF (cPAF) induced a robust activation of p21 that contributed to cell cycle arrest[20]
We noted that treating either HMC-1 cells or normal mast cells with cPAF suppressed the expression of DNA methyltransferases (DNMT) 1 and 3b, and we observed no difference in the methylation status of CpG islands in the promoter region of cPAF-treated mast cells[17]
Summary
The ultraviolet (UV) radiation in sunlight is the principal cause of both melanoma and non-melanoma skin cancer. We and others have provided evidence indicating that PAF plays an essential role in both UV-induced immune suppression and skin cancer induction[4,5,6,7,8,9]. P21 is a well-studied, potent inhibitor that binds to, and inhibits the activity of several cyclins and CDK complexes It belongs to the CIP/KIP family of cell cycle regulators and is implicated in many important and diverse regulatory functions of fundamental biological processes[21]. The profound effect PAF has on histone acetylation leading to CXCR4 expression in human mast cells[17] led us to question whether PAF modulated other genes at the epigenetic level. Given that p21 expression is usually regulated at the transcriptional level[31,32], and that one of the main events regulating transcriptional activation is histone acetylation, we decided to focus our attention on the possible effects of PAF on acetylation of p21
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