Factors linking inflammation and cancer are of great interest. Introduction Inflammation is a crucial protective response conserved in all multicellular organisms (Medzhitov, 2010). It entails activation of many cell types through several signaling pathways including nuclear factor kappa B (NF-B) and signal transducer and activator of transcription 3 (STAT3), resulting in release of cytokines and chemokines. Inflammation is tightly regulated and is effectively turned off when no longer needed (Lawrence et?al., 2001, ODea and Hoffmann, 2010). Malfunction of the shutdown machinery might result in chronic inflammation, promoting pathologies such as inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohns disease (Majno and Joris, Olmesartan 2004, Kumar and Robbins, 2007). Although proper inflammatory response may suppress cancer (Mantovani et?al., 2008), chronic inflammation can promote tumor initiation Olmesartan and progression (Brigati et?al., 2002, Pikarsky et?al., 2004, Grivennikov et?al., 2010, Schetter et?al., 2010, Ben-Neriah and Karin, 2011, Hanahan and Weinberg, 2011). Notably, IBD patients carry an increased cancer risk (Eaden et?al., 2001). NF-B transcription factors consist of different dimeric combinations of p50, p52, p65 (RelA), c-Rel, and RelB, binding DNA as either hetero- or homodimers (DiDonato et?al., 2012). Since only p65, c-Rel, and RelB contain transcriptional activation domains (TAD), dimers comprising these subunits can activate transcription while the others repress transcription Olmesartan unless they recruit specific co-activators (Heinz et?al., 2013, Kogure et?al., 2013). Additionally, NF-B regulates diverse processes such as apoptosis, cell proliferation, differentiation, and tumorigenesis (DiDonato et?al., 2012, Perkins, 2012). Eukaryotic DNA is packaged in nucleosomes consisting of four core histones (H2A, H2B, H3, and H4), which undergo many post-translational modifications (PTM) that control chromatin dynamics and transcription (Campos and Reinberg, 2009). One such PTM is monoubiquitylation of mammalian histone H2B on lysine 120 (H2Bub1), executed primarily by the RNF20 (hBRE1)/RNF40 E3 ligase complex (Hwang et?al., 2003). H2Bub1 resides mainly downstream to transcription start sites (TSS), in preferential association with highly transcribed genes (Minsky et?al., 2008). It participates in RNA polymerase II (RNA Pol II)-dependent transcription, cooperatively with the facilitates chromatin transcription (FACT) and polymerase-associated factor (PAF) complex (Pavri et?al., 2006). H2Bub1 can also negatively regulate transcription and may contribute to heterochromatin silencing (Zhang et?al., 2008). In HeLa cells, H2Bub1 modulates transcription of specific gene sets (Shema et?al., 2008): one subgroup, enriched in proto-oncogenes, is upregulated upon partial RNF20 depletion, while the other, including the p53 tumor suppressor, is downregulated. Furthermore, H2Bub1 impedes recruitment of TFIIS, a factor capable of relieving paused RNA Pol II (Shema et?al., 2011). Conversely, H2Bub1 upregulates other transcripts by favoring recruitment of the SWI/SNF chromatin remodeling complex (Shema-Yaacoby et?al., 2013). Notably, RNF20 displays tumor suppressor features (Shema et?al., 2008). Moreover, RNF20 and H2Bub1 are reduced in many cancers (Prenzel et?al., 2011, Chernikova et?al., 2012, Hahn et?al., 2012, Urasaki et?al., 2012, Thompson et?al., 2013, Wang et?al., 2013, Bedi et?al., 2014). H2Bub1 levels are low in both embryonic and adult stem cells but increase during differentiation and may be Rabbit polyclonal to ICAM4 a prerequisite for proper execution of the differentiation program (Fuchs et?al., 2012, Karpiuk et?al., 2012). Additionally, RNF20 and H2Bub1 are implicated in the DNA damage response, replication stress, and chromosomal stability (Kari et?al., 2011, Moyal et?al., 2011, Nakamura et?al., 2011, Shiloh et?al., 2011, Chernikova and Brown, 2012, Thompson et?al., 2013). H2Bub1 is coupled to ongoing transcription (Pavri et?al., 2006, Zhang et?al., 2008). Its modulation affects the transcriptional response to epidermal growth factor (EGF) (Shema et?al., 2008), estrogen (Prenzel et?al., 2011, Bedi et?al., 2014), interferon gamma (Buro et?al., 2010), and androgens (J??skel?inen et?al., 2012). We now report that RNF20 depletion, leading to decreased H2Bub1, augments the ability of the proinflammatory cytokine tumor necrosis factor alpha (TNF-) to upregulate a panel of inflammation-associated genes. Importantly, mice with reduced RNF20 and H2Bub1 are predisposed to chronic colonic inflammation. Notably, colons of UC patients tend to underexpress and mRNA, in conjunction with H2Bub1 downregulation in both epithelial and stromal compartments. Moreover, RNF20-low mice succumb preferentially to inflammation-associated colorectal cancer.