The ING4 tumor suppressor attenuates NF-kappaB activity at the promoters of target genes.
The NF-kappaB family mediates immune and inflammatory responses. In many cancers, NF-kappaB 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-kappaB is constitutively activated, ING4 expression is negligible, and NF-kappaB-regulated gene expression is elevated. We demonstrate that an ING4 and NF-kappaB interaction exists but does not prevent NF-kappaB activation, nuclear translocation, or DNA binding. Instead, ING4 and NF-kappaB bind simultaneously at NF-kappaB-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-kappaB target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-kappaB molecules that are bound to target gene promoters.
Nozell
Susan
S
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA. snozell@uab.edu
Laver
Travis
T
Moseley
Dorothy
D
Nowoslawski
Lisa
L
De Vos
Marijke
M
Atkinson
George P
GP
Harrison
Keith
K
Nabors
L Burton
LB
Benveniste
Etty N
EN
D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D005910:Glioma / Q000201:enzymology / Q000235:genetics*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D006657:Histones; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D020780:Matrix Metalloproteinase 9; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases
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