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 journalArticle

20 Scopus citations

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 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
Volume77
Issue number11
DOIs
Publication statusPublished - Jun 1 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Redd, P. S., Ibrahim, M. L., Klement, J. D., Sharman, S. K., Paschall, A. V., Yang, D., ... Liu, K. (2017). SETD1B activates iNOS expression in myeloid-derived suppressor cells. Cancer Research, 77(11), 2834-2843. https://doi.org/10.1158/0008-5472.CAN-16-2238