Platelet activating factor-induced expression of p21 is correlated with histone acetylation.
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.
Dipartimento di Scienze della Vita e dell'Ambiente, Universita' Politecnica delle Marche, Ancona, Italy.
Elisabetta
E
Damiani
Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Nahum
N
Puebla-Osorio
Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Bree M
BM
Lege
Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Jingwei
J
Liu
Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Sattva S
SS
Neelapu
Department of Immunology and The Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Graduate School for Biomedical Sciences at Houston, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Stephen E
SE
Ullrich
D000107:Acetylation; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D042421:Histone Code; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism
C493956:CDKN1A protein, human; C527276:CXCR4 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010972:Platelet Activating Factor; D019718:Receptors, CXCR4