Identification of the upstream regulators of interferon regulatory factor 4 (IRF4) expression in melanoma cells

Abstract

Melanoma is derived from melanin pigment producing cells which are known as melanocytes. Late stage, metastatic melanoma is considered as one of the most aggressive malignancies with one of the worst prognosis. IRF4 belongs to interferon regulatory family member transcriptional regulators. IRF4 expression, which is regulated by mitogenic stimuli such as NF-κB in lymphocytes, is associated with certain cancers such as T-cell leukemia, multiple myeloma and B cell lymphoma. In addition to immune cell derived malignancies, IRF4 overexpression is found in melanoma cell lines and melanoma patient samples. Additionally, dependency of melanoma cell lines to IRF4 expression was recently found. Moreover, genome wide association studies (GWAS) identified a SNP in IRF4 locus as high risk factor for melanoma. The aim of this project is to find out how IRF4 expression is regulated, and which pathways are playing role in its overexpression in melanoma. Insights into IRF4 regulation holds promise for new therapeutic intervention strategies for melanoma. Most of our knowledge about upstream regulators of IRF4 comes from hematologic cells. Based on known regulators of IRF4 in these cells, we choose three pathways as candidate regulators of IRF4 expression in melanoma cells. Using small molecular compounds, we modulated the activities of these pathways. We used luciferase transactivation assays in order to prove the efficacy of these small molecules. Then we checked IRF4 expression at both mRNA and protein levels in treated cells. Our results suggest that one of these lymphocyte-related signaling pathways plays role in IRF4 expression in melanoma cells.