title: Levuglandin forms adducts with histone h4 in a cyclooxygenase-2-dependent manner, altering its interaction with DNA.
abstract: Inflammation and subsequent cyclooxygenase-2 (COX-2) activity has long been linked with the development of cancer, although little is known about any epigenetic effects of COX-2. A product of COX-2 activation, levuglandin (LG) quickly forms covalent bonds with nearby primary amines, such as those in lysine, which leads to LG-protein adducts. Here, we demonstrate that COX-2 activity causes LG-histone adducts in cultured cells and liver tissue, detectable through LC-MS, with the highest incidence in histone H4. Adduction is blocked by a γ-ketoaldehyde scavenger, which has no effect on COX-2 activity as measured by PGE2 production. Formation of the LG-histone adduct is associated with an increased histone solubility in NaCl, indicating destabilization of the nucleosome structure; this is also reversed with scavenger treatment. These data demonstrate that COX-2 activity can cause histone adduction and loosening of the nucleosome complex, which could lead to altered transcription and contribute to carcinogenesis.
authors.affiliation: Departments of †Pharmacology, ‡Pathology, and §Medicine, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Carrier
authors.forename: Irene
authors.initials: I
authors.lastname: Zagol-Ikapitte
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Amarnath
authors.forename: Olivier
authors.initials: O
authors.lastname: Boutaud
authors.forename: John A
authors.initials: JA
authors.lastname: Oates
mesh_terms: D002853:Chromatography, Liquid; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D006657:Histones / Q000737:chemistry*; D013058:Mass Spectrometry; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry; D011458:Prostaglandins E / Q000737:chemistry*; D012995:Solubility
chemical_list: D006657:Histones; D011458:Prostaglandins E; C570744:levuglandin D2; D004247:DNA; C047684:levuglandin E2; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2