Journal
BIOCHEMISTRY
Volume 53, Issue 15, Pages 2436-2441Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi401673b
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Funding
- Center for Molecular Toxicology, NIH [P30 ES000267]
- American Cancer Society [PF-09-127-01-DMC]
- [GM15431]
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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 gamma-ketoaldehyde scavenger, which has no effect on COX-2 activity as measured by PGE(2) 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.
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