SETD1B activates iNOS expression in myeloid-derived suppressor cells

Priscilla S. Redd, Mohammed L. Ibrahim, John D. Klement, Sarah K. Sharman, Amy V. Paschall, Dafeng Yang, Asha Nayak-Kapoor, Kebin Liu

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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 cells in vivo. Strikingly, 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.

Original languageEnglish (US)
Pages (from-to)2834-2843
Number of pages10
JournalCancer Research
Issue number11
StatePublished - Jun 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'SETD1B activates iNOS expression in myeloid-derived suppressor cells'. Together they form a unique fingerprint.

Cite this