EPIGENETIC REGULATION OF CYTOSOLIC PHOSPHOLIPASE A2

Abstract

Cytosolic phospholipase A2 (cPLA2 or PLA2G4A) contributes to inflammation. In this study, treatment with histone deacetylase inhibitors, trichostatin A, valproic acid, tubacin and MS-275 increased cPLA2a mRNA expression in SH-SY5Y cells. Co-treatment of the histone acetyltransferase inhibitor, anacardic acid, modulated upregulation of cPLA2a induced by TSA. Specific involvement of class I HDACs and HAT in cPLA2a regulation was further shown, and a Tip60-specific HAT inhibitor, NU9056, modulated the upregulation of cPLA2a induced by MS-275. In addition, co-treatment of with histone methyltransferase (HMT) inhibitor, 5'-deoxy-5'-methylthioadenosine suppressed TSA-induced cPLA2a upregulation. Changes were reflected at the protein level by Western blots and immunocytochemistry. Chromatin immunoprecipitation showed TSA increased binding of trimethylated H3K4 to the proximal promoter region of the cPLA2a gene. Cell injury after TSA treatment as indicated by lactate dehydrogenase release was modulated by anacardic acid, and a role of cPLA2 in mediating TSA-induced injury shown, after co-incubation with the cPLA2 selective inhibitor, arachidonoyl trifluoromethyl ketone. Together, results indicate epigenetic regulation of cPLA2 and the potential of such regulation for treatment of chronic inflammation.