AP-1 Mediated Transcriptional Repression of Matrix Metalloproteinase-9 by Recruitment of Histone Deacetylase 1 in Response to Interferon b

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-b (IFNb) 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 IFNb in HT1080 fibrosarcoma cells. Using reporter assays with promoter deletion constructs we show that IFNb’s inhibitory effects require a region of the promoter between 2154 and 272, which contains an AP-1 binding site. Chromatin immunoprecipitation (ChIP) studies indicate that IFNb increases histone deacetylase (HDAC)-1 recruitment to the MMP-9 promoter and reduces histone H3 acetylation, in addition to reduced NF-kB recruitment. ChIP analysis shows that IFNb induced HDAC1 recruitment to the MMP-9 promoter and IFNb 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 IFNb occurs by the recruitment of HDAC1 via the proximal AP-1 binding site