Inhibitor of growth-4 promotes IκB promoter activation to suppress NF-κB signaling and innate immunity

Abstract

Ing4 is a member of the inhibitor of growth (ING) family of chromatin-modifying proteins. Biochemical experiments indicate that Ing4 is a subunit of the HB01-JADE-hEAF6 histone acetyltransferase complex responsible for most nucleosomal histone H4 acetylation in eukaryotes, and transfection studies suggest that Ing4 may regulate a wide variety of cellular processes, including DNA repair, apoptosis, cell-cycle regulation, metastasis, angiogenesis, and tumor suppression. However, in vivo evidence for a physiological role for Ing4 in cell-growth regulation is lacking. We have generated Ing4-deficient mice to explore the role of Ing4 in development, tumorigenesis, and in NF-κB signaling. Ing4-null mice develop normally and are viable. Although mice deficient for Ing4 fail to form spontaneous tumors, they are hypersensitive to LPS treatment and display elevated cytokine responses. Macrophages isolated from Ing4-null mice have increased levels of nuclear p65/RelA protein, resulting in increased RelA binding to NF-κB target promoters and up-regulation of cytokine gene expression. However, increased promoter occupancy by RelA in LPS-stimulated, Ing4-null cells does not always correlate with increased NF-κB target-gene expression, as RelA activation of a subset of cytokine promoters also requires Ing4 for proper histone H4 acetylation. Furthermore, activation of the IκBα promoter by RelA is also Ing4-dependent, and LPS-stimulated, Ing4-null cells have reduced levels of IκBα promoter H4 acetylation and IκB gene expression. Thus, Ing4 negatively regulates the cytokine-mediated inflammatory response in mice by facilitating NF-κB activation of IκB promoters, thereby suppressing nuclear RelA levels and the activation of select NF-κB target cytokines.

Chromatin Memory in the Development of Human Cancers

“…Global and/or gene-specific histone covalent modifications change accompanied by alterations of enzymes associated with those marks is an epigenetic hallmark that is frequently found in tumor cells, similar alterations have also been found in carcinogen exposed cells [109].…”

Role of ING Family Tumor Suppressors in Breast Cancer

“…p37Ing1 in mice regulated Bax levels in a negative way and worked as a prosurvival molecule following DNA damage independent of p53 status, complicating the function of ING1 in mouse and human and in various other circumstances. Moreover, recent experiments have also suggested that there are p53-independent functions for the ING proteins, including regulation of the NF-kB and hypoxia inducible factor (HIF) pathways [49][50][51][52]. ING2 shows a high rate of homology with ING1 about 70% [9,10,30,34,53].…”

MicroRNA-650 in a copy number-variable region regulates the production of interleukin 6 in human osteosarcoma cells

“…Regulation of NFκB activity by ING4 may be due to a physical interaction between ING4 and p65 (RelA), a subunit of NFκB, that results in decreased activation of the canonical NFκB-responsive promoter in brain tumor cells (30). A previous study showed that ING4 promotes IκB promoter activation to suppress NFκB signaling (35). The present study did not investigate whether ING4 directly interacted with p65 or how ING4 regulates the NFκB signaling pathway to induce the differential expression of NFκB target genes.…”