Chronic inflammation is known to mediate and affect cancer progression and is evoked by many different extracellular stimuli, such as cytokines. One of the main cytokines involved in inflammation is the tumor necrosis factor α (TNF-α) and its downstream signaling cascade, the NF-κB pathway. When activated, the NF-κB pathway leads to the transcription of its target genes, a processes mediated through many coactivators and histone modifications. RNF20 is an E3 ubiquitin ligase that monoubiquitylates histone H2B, and was shown to play a pivotal role in transcription regulation of a subset of genes. Specifically, RNF20 was shown to repress the transcription of EGF–inducible genes. Interestingly, one of the RNF20-repressed genes revealed in HeLa cells was IL-8, also known to be a major target gene of the NF-κB pathway. This observation led to the hypothesis that RNF20 may share a molecular interplay with NF-κB. The aim of this study was to explore a possible cross talk between the two factors, and more generally to investigate the connection between inflammation-driven cancer and RNF20. In this study I identified a role for RNF20 in regulating the inflammatory response mediated through NF-κB. Intriguingly, RNF20 reduced NF-κB dependent transcription in MCF10A cells. I also identified a possible mechanism, in which RNF20 promotes the binding of the NF-κB subunit p50 to target gene promoters, thus mediating target gene transcription. Additionally, in RNF20 heterozygous mice, more severe acute and chronic inflammation were evident after dextran sodium sulfate (DSS) treatment, and DSS treatment combined with AOM caused development of more tumors in RNF20 heterozygous mice compared to WT mice. Taken together, my results demonstrate that RNF20 may be an important regulator of acute and chronic inflammation, and an important inhibitor of inflammation-induced cancer.
