title: AP-1 mediated transcriptional repression of matrix metalloproteinase-9 by recruitment of histone deacetylase 1 in response to interferon β.
abstract: Matrix metalloproteinase-9 (MMP-9) is a 92 kDa zinc-dependant endopeptidase that degrades components of the extracellular matrix. Increased expression of MMP-9 is implicated in many pathological conditions including metastatic cancer, multiple sclerosis, and atherosclerosis. Although it has been widely noted that interferon-β (IFNβ) downregulates both the basal and phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 expression at the transcriptional level, the molecular mechanism of this repression is poorly understood. In the present study we identify a novel mechanism for repression of MMP-9 transcription by IFNβ in HT1080 fibrosarcoma cells. Using reporter assays with promoter deletion constructs we show that IFNβ's inhibitory effects require a region of the promoter between -154 and -72, which contains an AP-1 binding site. Chromatin immunoprecipitation (ChIP) studies indicate that IFNβ increases histone deacetylase (HDAC)-1 recruitment to the MMP-9 promoter and reduces histone H3 acetylation, in addition to reduced NF-κB recruitment. ChIP analysis shows that IFNβ induced HDAC1 recruitment to the MMP-9 promoter and IFNβ mediated transcriptional repression is lost when the AP-1 binding site is inactivated by a point mutation. Altogether, our results establish that the repression of MMP-9 transcription in response to IFNβ occurs by the recruitment of HDAC1 via the proximal AP-1 binding site.
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, United States of America.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Mittelstadt
authors.forename: Rekha C
authors.initials: RC
authors.lastname: Patel
mesh_terms: D020029:Base Pairing / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D016899:Interferon-beta; D020780:Matrix Metalloproteinase 9; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1