Suppression of IRF4 by IRF1, 3, and 7 in Noxa Expression Is a Necessary Event for IFN-γ–Mediated Tumor Elimination

Abstract

IFN-g plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up-and downregulated Noxa expression, a prodeath BH3 protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-g is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPSinduced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-g might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-g and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-g alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-g, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity. Mol Cancer Res; 9(10); 1356-65. Ó2011 AACR.

UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition

“…Indeed, EZH2i treatment of ARD but not ARP-1 cells induced the expression of BCL6, IRF1 and BATF transcription factors (Fig. 5E, 6F-G), all reported to repress IRF4 expression (Ci et al, 2009, Piya et al, 2011, Kurachi et al, 2014). To ascertain the underlying cause of BCL6 exclusive activation in UTX -null cells upon treatment with EZH2i, we performed ChIP for H3K27me3 and H3K27ac in ARD and ARP-1 cells.…”

Loss of Interleukin Receptor-Associated Kinase 4 Signaling Suppresses Amyloid Pathology and Alters Microglial Phenotype in a Mouse Model of Alzheimer's Disease

“…IRF3 expression has been shown to be induced by IFNγ and be neuroprotective in the CNS (Koziczak-Holbro et al, 2008; Piya et al, 2011; Tarassishin et al, 2011). IRF7 is also crucial to the interferon response (Honda et al, 2005b; Nakajima et al, 2009; Ning et al, 2011) and upregulation of IRF7 in vivo has been shown to play a protective role in the CNS (Honda and Taniguchi, 2006; Salem et al, 2011).…”

Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus

“…In vitro, IRF-1 can bind to the same regulatory sites as Blimp-1 (34); however, the relevance of this observation has not been tested in vivo. IRF-1 opposes IRF-4-mediated gene regulation in cancer and mouse kidney cells (35); however, it is not clear whether this also happens during B cell differentiation. In this study, we observed a slight but statistically significant increase in the germinal center B cell population in naive IRF-1 Ϫ/Ϫ mouse spleens.…”