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Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-kappaB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes.
Constitutive nuclear factor (NF)-kappaB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-kappaB inhibitory molecules such as IkappaBalpha or p100. Hut-78, a truncated form of p100, constitutively generates p52 and contributes to the development of T-cell lymphomas but the molecular mechanism underlying this oncogenic potential remains unclear. We show here that MMP9 gene expression is induced through the alternative NF-kappaB-activating pathway in fibroblasts and also on Hut-78 or p52 overexpression in fibroblasts as well as in lymphoma cells. p52 is critical for Hut-78-mediated MMP9 gene induction as a Hut-78 mutant as well as other truncated NF-kappaB2 proteins that are not processed into p52 failed to induce the expression of this metalloproteinase. Conversely, MMP9 gene expression is impaired in p52-depleted HUT-78 cells. Interestingly, MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IkappaBalpha promoter, and the H3K4 trimethyltransferase activity recruited on the MMP9 promoter is impaired in p52-depleted HUT-78 cells. Moreover, MLL1 and MLL2 are associated with Hut-78 in a native chromatin-enriched extract. Thus, we identified a molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-kappaB-dependent gene induces its expression and potentially the invasive potential of lymphoma cells harbouring constitutive activity of the alternative NF-kappaB-activating pathway.
Amino Acid Sequence, Animals, Base Sequence, Cells, Cultured, DNA-Binding Proteins/metabolism, DNA-Binding Proteins/physiology, Enzyme Induction/drug effects, Enzyme Induction/physiology, Hela Cells, Histone-Lysine N-Methyltransferase, Humans, Lysine/metabolism, Matrix Metalloproteinase 9/biosynthesis, Matrix Metalloproteinase 9/genetics, Mice, Molecular Sequence Data, Multiprotein Complexes/metabolism, Multiprotein Complexes/physiology, Mutant Proteins/pharmacology, Myeloid-Lymphoid Leukemia Protein/metabolism, Myeloid-Lymphoid Leukemia Protein/physiology, NF-kappa B p52 Subunit/chemistry, NF-kappa B p52 Subunit/pharmacology, NIH 3T3 Cells, Neoplasm Proteins/metabolism, Neoplasm Proteins/physiology, Oncogene Proteins, Fusion/pharmacology, Protein Methyltransferases/metabolism, Protein Methyltransferases/physiology, Sequence Homology, Amino Acid
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