Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through direct interactions with the promoter via a mechanism, which is both dependent on and independent of histone deacetylation.
Although the expression of the metastases-associated gene MTA1 correlates with tumor metastases, its role in regulating type IV collagenase expression is unknown. Enforced MTA1 expression in HT1080 cells reduced basal and 12-myristate 13-acetate-induced 92-kDa type IV collagenase (MMP-9) protein/mRNA levels. DNase I hypersensitivity and PstI accessibility assays revealed multiple regions ... of the MMP-9 promoter (-650/-450 and -120/+1), showing reduced hypersensitivity in the MTA1-expressing cells. Chromatin immunoprecipitation assays demonstrated MTA1 binding to the distal region, which spans several regulatory cis elements. Co-immunoprecipitation and chromatin immunoprecipitation assay experiments revealed histone deacetylase 2 (HDAC2)-MTA1 protein-protein interactions and the MTA1-dependent recruitment of HDAC2 to the distal MMP-9 promoter region, yielding diminished histone H3/H4 acetylation. However, HDAC2 binding and H3/H4 acetylation at the proximal MMP-9 region were unaffected by MTA1 expression. Furthermore, trichostatin treatment only partially relieved MTA1-repressed MMP-9 expression, indicating a HDAC-insensitive component possibly involv ing the nucleosome-remodeling Mi2 activity, which was recruited to the promoter by MTA1. In summary, (a) MMP-9 adds to a short list of MTA1-regulated genes, which so far only includes c-myc and pS2, and (b) MTA1 binds to the MMP-9 promoter, thereby repressing expression of this type IV collagenase via histone-dependent and independent mechanisms.
Mesh Terms:
Acetylation, Chromatin, Deoxyribonuclease I, Histone Deacetylase 2, Histone Deacetylases, Histones, Humans, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Models, Genetic, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Proteins, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Tumor Cells, Cultured
Acetylation, Chromatin, Deoxyribonuclease I, Histone Deacetylase 2, Histone Deacetylases, Histones, Humans, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Models, Genetic, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Proteins, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Tumor Cells, Cultured
J. Biol. Chem.
Date: Jan. 24, 2003
PubMed ID: 12431981
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