Modulation of IFN-γ Receptor 1 Expression by AP-2α Influences IFN-γ Sensitivity of Cancer Cells

Interferon (IFN)-gamma plays crucial roles in regulating both innate and adaptive immunity. The existence of IFN-gamma receptor 1 (IFNGR1) molecules on the cell surface is a prerequisite to the initiation of IFN-gamma signaling; low expression of IFNGR1 leads to a functional blockade of IFN-gamma signaling. However, the molecular mechanisms by which IFNGR1 expression is controlled are unclear. In the present study, we demonstrated that IFNGR1 expression was reduced or lost in breast cancer. Heterogeneous IFNGR1 immunoreactivity appeared to be associated with the morphological heterogeneity of breast cancer, and loss of IFNGR1 expression was predominantly observed in poorly differentiated areas. We identified the functional activating protein (AP)-2 and specificity protein (SP)-1 sites within the IFNGR1 promoter. Ectopic expression of AP-2 alpha drastically repressed the expression of IFNGR1 and hindered IFN-gamma signaling, whereas AP-2 alpha gene silencing elevated IFNGR1 levels. Overexpression of SP-1 effectively antagonized the repressive effects of AP-2 alpha. Simultaneous recruitment of both transcription factors to the AP-2 and SP-1 motifs, respectively, in the IFNGR1 promoter was demonstrated, implying that AP-2 alpha and SP-1 may synergistically modulate IFNGR1 transcription. Moreover, AP-2 alpha overexpression in AP-2 deficient SW480 cells remarkably inhibited Stat1 phosphorylation and the anti-proliferative effects of IFN-gamma, whereas knockdown of the AP-2 alpha expression dramatically enhanced the sensitivities of HeLa cells highly expressing AP-2 to IFN-gamma, indicating that dysregulation of AP-2 alpha expression is associated with impaired IFN-gamma actions in cancer cells. (Am J Path, 2012, 180:661-671; DOI: 10.1016/j.ajpath.2011.10.040)