title: SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells.
abstract: Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1-and immature CD11b+Gr1+myeloid cellsin vivoStrikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions.Cancer Res; 77(11); 2834-43. ©2017 AACR.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.|Georgia Cancer Center, Augusta University, Augusta, Georgia.|Charlie Norwood VA Medical Center, Augusta, Georgia.
authors.forename: Priscilla S
authors.initials: PS
authors.lastname: Redd
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.|Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Mohammed L
authors.initials: ML
authors.lastname: Ibrahim
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.|Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: John D
authors.initials: JD
authors.lastname: Klement
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.|Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Sharman
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.|Georgia Cancer Center, Augusta University, Augusta, Georgia.|Charlie Norwood VA Medical Center, Augusta, Georgia.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Paschall
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.|Charlie Norwood VA Medical Center, Augusta, Georgia.
authors.forename: Dafeng
authors.initials: D
authors.lastname: Yang
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Charlie Norwood VA Medical Center, Augusta, Georgia.
authors.forename: Asha
authors.initials: A
authors.lastname: Nayak-Kapoor
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia. Kliu@augusta.edu.|Georgia Cancer Center, Augusta University, Augusta, Georgia.|Charlie Norwood VA Medical Center, Augusta, Georgia.
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase