The role of multiple coactivators in human matrix metalloproteinase-9 gene expression

B43

Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent endopeptidase with broad substrates from extracellular matrix proteins to bioactive molecules. It regulates physiological processes such as tissue remodeling and immune responses. However, MMP-9 exacerbates the development of cancers and inflammatory diseases due to its aberrant upregulation. Therefore, MMP-9 has been under intensive study as a cancer therapeutic target. In order to control MMP-9 expression in cancers, understanding the regulatory mechanisms of MMP-9 expression is required. MMP-9 gene expression is regulated mainly at the transcriptional level. In this study, we determined the involvement of multiple transcriptional coactivators in MMP-9 transcription. Our data indicate that coactivators from different groups including CBP/p300, PCAF, CARM1 and GRIP1 are able to activate MMP-9 promoter activity. This enhancement requires the histone acetyltransferase activity of PCAF but not that of CBP/p300, and the methyltransferase activity of CARM1. Furthermore, MMP-9 promoter transcription is synergistically activated by coexpression of p300, CARM1 and GRIP1. This substantial synergy depends on the interaction of p300 and CARM1 with the AD1 and AD2 domains of GRIP1, respectively. These results support the model that these three coactivators form a ternary complex on the MMP-9 promoter. More importantly, these coactivators are associated with the endogenous MMP-9 promoter as shown by chromatin immunoprecipitation assays. SiRNA knockdown of p300, CARM1 and GRIP1 greatly reduced endogenous MMP-9 expression. Collectively, our study illustrates the importance of coactivators for MMP-9 expression, and suggest that knockdown of coactivators is an effective way to decrease MMP-9 expression, which may be particularly useful in breast and prostate cancers, where coactivators are overexpressed.