The ING4 Tumor Suppressor Attenuates NF-κB Activity at the Promoters of Target Genes

The NF-kappa B family mediates immune and inflammatory responses. In many cancers, NF-kappa B is constitutively activated and induces the expression of genes that facilitate tumorigenesis. ING4 is a tumor suppressor that is absent or mutated in several cancers. Herein, we demonstrate that in human gliomas, NF-kappa B is constitutively activated, ING4 expression is negligible, and NF-kappa B-regulated gene expression is elevated. We demonstrate that an ING4 and NF-kappa B interaction exists but does not prevent NF-kappa B activation, nuclear translocation, or DNA binding. Instead, ING4 and NF-kappa B bind simultaneously at NF-kappa B-regulated promoters, and this binding correlates with reductions in p65 phosphorylation, p300, and the levels of acetylated histones and H3-Me3K4, while enhancing the levels of HDAC-1 at these promoters. Using a knockdown approach, we correlate reductions in ING4 protein levels with increased basal and inducible NF-kappa B target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-kappa B molecules that are bound to target gene promoters.