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

Abstract

The NF-B family mediates immune and inflammatory responses. In many cancers, NF-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-B is constitutively activated, ING4 expression is negligible, and NF-B-regulated gene expression is elevated. We demonstrate that an ING4 and NF-B interaction exists but does not prevent NF-B activation, nuclear translocation, or DNA binding. Instead, ING4 and NF-B bind simultaneously at NF-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-B target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-B molecules that are bound to target gene promoters.

Reduced expression and prognostic implication of inhibitor of growth 4 in human osteosarcoma

“…Instead, it was noted that the degree of reduction in ING4 expression correlated with the progression from low to high grades of osteosarcoma, according to the Enneking classification system for malignant bone tumors (P=0.002). ING4, a novel tumor suppressor of the ING family, has potential tumor-suppressing effects that are exerted through various signaling pathways, including tumorigenesis, cell cycle regulation, angiogenesis, cell apoptosis, DNA repair, migration and transcriptional regulation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(37)(38)(39)(40)(41)(42)(43). These functions of ING4, which acts as an oncogene suppressor in numerous tumor types, have been identified repeatedly in vitro and in vivo (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(37)(38)…”

“…The inhibition of NF-κB negatively regulates various target genes, including matrix metalloproteinase (MMP)-2, MMP-9, interleukin (IL)-6, IL-8, cyclooxygenase-2 and colony stimulating factor-3. The downregulation of these cytokines inhibits angiogenesis and tumor cell growth (11)(12)(13)(14)(15). In RKO colorectal cancer cells, ING4 expression was able to decrease the cell population in the S-phase of the cell cycle in a p53-dependent manner, as well as upregulate p21 expression (16).…”

ING4 inhibits the translation of proto‐oncogene MYC by interacting with AUF1

“…ING4 participates in transcriptional regulation via its interaction with various DNA-binding proteins, such as p53, the p65(RelA) NF-rB subunit, and hypoxiainducible factor 1-a (HIF1) [8,10,11]. ING4 was also co-purified with the HBO1/JADE histone acetyltransferase (HAT) complex that is involved in chromatin modification and activation of transcription in response to DNA damage [26].…”

“…ING4 contains a novel conserved region (NCR) in the N terminus, a nuclear localization signal (NLS) in the central region, and a highly conserved plant homeodomain (PHD) in the C terminus [1]. Previous studies suggest that many functions of ING4 rely on its association with other proteins [8][9][10][11]. ING4 binds to p53 and p300, and enhances the transcription activity of p53 [8].…”

A novel NFIA-NFκB feed-forward loop contributes to glioblastoma cell survival

“…[15][16][17][18] NFκB activation in cancer may be the result of either exposure to pro-inflammatory stimuli, such as tumor necrosis factor (TNF), or upregulation of signaling from upstream regulators. [19][20][21][22] NFκB is constitutively active in many cancers, including gliomas, [23][24][25] and aberrant regulation of NFκB signaling is involved in apoptosis evasion and tumor promotion. 26 In GBM, elevated NFκB signaling is associated with enhanced chemo-and radiation resistance in the mesenchymal subtype.…”