Interferon-gamma-induced suppression of S100A4 transcription is mediated by the class II transactivator

We have previously shown that interferon-gamma (IFN-gamma) inhibits expression of the metastasis-promoting protein S100A4. In the present study, we further explore the mechanism behind the IFN-gamma-mediated effects on the human S100A4 promoter and demonstrate that IFN-gamma represses S100A4 promoter activity through induction of the class II transactivator (CIITA). The acidic domain in the N-terminal part of CIITA was crucial for the observed IFN-gamma-induced inhibition of S100A4 promoter activity, probably by binding the histone acetyltransferase CBP/p300. Importantly, overexpression of CIITA significantly reduced the expression of endogenous S100A4. Our data suggest a model where CIITA represses S100A4 transcription through sequestering of CBP/p300, thereby reducing the level of CBP/p300 at the S100A4 promoter, which in turn leads to inhibition of S100A4 transcription.