The proto-oncogene Bcl3 is an atypical member of IkB family, which regulates expression of a number of NFkB target genes, including anti-apoptotic genes, cytokines, and immune checkpoints. Bcl3 expression is increased in many types of human cancers and is associated with increased tumor growth and malignant potential. Interferon-γ (IFNγ) is a pleiotropic cytokine that has been used in cancer treatment; in addition, its expression is induced in response to radiation therapy and immune checkpoint blockade during cancer treatment. We have recently shown that IFNγ induces Bcl3 expression in ovarian cancer cells, resulting in their increased proliferation, migration, and invasion. In this study, we have investigated the mechanisms of how IFNγ induces the Bcl3 expression in ovarian cancer cells. Our results demonstrate that the IFNγ-induced Bcl3 expression is dependent on JAK1 and STAT1 signaling, as well as on p65 NFkB. In addition, we have identified a potential interferon regulatory factor 1 (IRF1) binding site in human Bcl3 promoter and found that the IFNγ-induced Bcl3 expression in ovarian cancer cells is associated with an increased occupancy of IRF1, Ser-727 phosphorylated STAT1 and acetylated histone H3 at the IRF1 binding site in Bcl3 promoter. These findings identify Bcl3 as a novel target of IFNγ/JAK1/STAT1 signaling and suggest that targeting the JAK1/STAT1 pathway may suppress the IFNγ-induced Bcl3 expression in ovarian cancer.
