Interferon Regulatory Factor 4 Modulates Epigenetic Silencing and Cancer-Critical Pathways in Melanoma Cells

Interferon Regulatory Factor 4 (IRF4) is a transcription factor initially identified as a key controller in lymphocyte differentiation and function, and subsequently as a dependency factor and therapy target in lymphocyte-derived cancers. In melanocytes, IRF4 takes part in the regulation of pigmentation. While numerous genetic studies have implicated IRF4 also in melanoma skin cancers, how IRF4 contributes to melanoma has remained largely elusive. In this study, we first confirmed that not only IRF4 expression is common in melanoma, but also IRF4 can act as a dependency factor for melanoma cells. Furthermore, to discover the functions of IRF4 in melanoma cells, we analyzed IRF4 target genes, which pointed to IRF4 as an upstream regulator of epigenetic silencing. Accordingly, we show that IRF4 regulates the expression of essential factors for DNA methylation (DNMT1, DNMT3B, UHFR1) and for repressive histone H3 lysine 27 methylation (EZH2), and consequently, the levels of the corresponding methylation marks. Moreover, expression of several tumor suppressor genes known to be silenced by these epigenetic modifications are regulated by IRF4. These include cyclin-dependent kinase inhibitors, PI3K pathway regulator PTEN, and primary cilium component WDR19. As a result, IRF4-dependent epigenetic regulation in melanoma cells modulates the activity of key oncogenic pathways, such as WNT/b-Catenin and PI3K-AKT, impacting on cell proliferation and survival. Moreover, IRF4 modulates the activity of pertinent epigenetic drugs in melanoma cells, encouraging further studies on the therapeutic targeting of IRF4 in melanoma.