title: Nitric Oxide Regulates Gene Expression in Cancers by Controlling Histone Posttranslational Modifications.
abstract: Altered nitric oxide (•NO) metabolism underlies cancer pathology, but mechanisms explaining many •NO-associated phenotypes remain unclear. We have found that cellular exposure to •NO changes histone posttranslational modifications (PTM) by directly inhibiting the catalytic activity of JmjC-domain containing histone demethylases. Herein, we describe how •NO exposure links modulation of histone PTMs to gene expression changes that promote oncogenesis. Through high-resolution mass spectrometry, we generated an extensive map of •NO-mediated histone PTM changes at 15 critical lysine residues on the core histones H3 and H4. Concomitant microarray analysis demonstrated that exposure to physiologic •NO resulted in the differential expression of over 6,500 genes in breast cancer cells. Measurements of the association of H3K9me2 and H3K9ac across genomic loci revealed that differential distribution of these particular PTMs correlated with changes in the level of expression of numerous oncogenes, consistent with epigenetic code. Our results establish that •NO functions as an epigenetic regulator of gene expression mediated by changes in histone PTMs.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Divya
authors.initials: D
authors.lastname: Vasudevan
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Hickok
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Rhea C
authors.initials: RC
authors.lastname: Bovee
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Vy
authors.initials: V
authors.lastname: Pham
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York.
authors.forename: Lin L
authors.initials: LL
authors.lastname: Mantell
authors.affiliation: Center for Research Informatics, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Neil
authors.initials: N
authors.lastname: Bahroos
authors.affiliation: Center for Research Informatics, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Pinal
authors.initials: P
authors.lastname: Kanabar
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xing-Jun
authors.initials: XJ
authors.lastname: Cao
authors.affiliation: Center for Research Informatics, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Mark
authors.initials: M
authors.lastname: Maienschein-Cline
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois. ddthomas@uic.edu.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Thomas
mesh_terms: D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006657:Histones / Q000235:genetics*; D006801:Humans; D013058:Mass Spectrometry; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational / Q000235:genetics*
chemical_list: D006657:Histones; D009569:Nitric Oxide