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Related Experiment Videos

SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells.

Priscilla S Redd1,2,3, Mohammed L Ibrahim1,2, John D Klement1,2

  • 1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.

Cancer Research
|April 7, 2017
PubMed
Summary

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Tumor cells hijack the SETD1B-H3K4me3 epigenetic pathway to increase inducible nitric oxide synthase (iNOS) in myeloid-derived suppressor cells (MDSCs), suppressing anti-tumor immunity. This IRF8-independent mechanism bypasses normal iNOS regulation in cancer.

Area of Science:

  • Immunology
  • Epigenetics
  • Cancer Biology

Background:

  • Inducible nitric oxide synthase (iNOS) produces nitric oxide (NO), a key mediator in immune responses against pathogens and tumors.
  • Myeloid-derived suppressor cells (MDSCs) are crucial in tumor-induced immunosuppression, partly through elevated iNOS expression.
  • The regulatory mechanisms of iNOS in tumor-associated MDSCs remain poorly understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms controlling iNOS expression in tumor-induced MDSCs.
  • To investigate the role of IRF8 and epigenetic factors in regulating iNOS in MDSCs under tumor conditions.

Main Methods:

  • Analysis of iNOS expression in myeloid cells from tumor-bearing and tumor-free mice.
  • Investigating the role of IRF8, STAT1, NF-κB, and SETD1B in iNOS regulation.

Related Experiment Videos

  • Utilizing chromatin immunoprecipitation (ChIP) to assess H3K4me3 enrichment at the nos2 promoter.
  • Employing SETD1B inhibition and silencing to evaluate its impact on iNOS expression.

    • Main Results:

    • IRF8 deficiency led to reduced iNOS expression in myeloid cells, but iNOS was elevated in tumor-induced MDSCs despite IRF8 silencing.
    • Tumor-induced MDSCs showed decreased levels of STAT1 and NF-κB, key iNOS inducers.
    • SETD1B expression was increased in tumor-induced MDSCs, correlating with enriched H3K4me3 at the nos2 promoter.
    • Inhibition or silencing of SETD1B significantly reduced iNOS expression in tumor-induced MDSCs.

    Conclusions:

    • Tumor cells exploit an IRF8-independent epigenetic mechanism involving SETD1B and H3K4me3 to upregulate iNOS in MDSCs.
    • This pathway contributes to the immunosuppressive environment in tumors by enhancing NO production.
    • Targeting the SETD1B-H3K4me3 axis may offer a novel strategy to restore anti-tumor immunity.