RNF20 Links Histone H2B Ubiquitylation with Inflammation and Inflammation-Associated Cancer

Summary Factors linking inflammation and cancer are of great interest. We now report that the chromatin-targeting E3 ubiquitin ligase RNF20/RNF40, driving histone H2B monoubiquitylation (H2Bub1), modulates inflammation and inflammation-associated cancer in mice and humans. Downregulation of RNF20 and H2Bub1 favors recruitment of p65-containing nuclear factor κB (NF-κB) dimers over repressive p50 homodimers and decreases the heterochromatin mark H3K9me3 on a subset of NF-κB target genes to augment their transcription. Concordantly, RNF20+/− mice are predisposed to acute and chronic colonic inflammation and inflammation-associated colorectal cancer, with excessive myeloid-derived suppressor cells (MDSCs) that may quench antitumoral T cell activity. Notably, colons of human ulcerative colitis patients, as well as colorectal tumors, reveal downregulation of RNF20/RNF40 and H2Bub1 in both epithelium and stroma, supporting the clinical relevance of our tissue culture and mouse model findings.
Graphical Abstract
Highlights • RNF20 and H2Bub1 modulate the NF-kB response • RNF20-deficient mice are prone to colonic inflammation and colorectal cancer • Reduced H2Bub1 may create a pro-tumoral microenvironment • Reduced H2Bub1 is associated with colitis and colorectal cancer in humans
Ubiquitination of histone H2B (H2Bub1), primarily by the E3 ligase RNF20, is reduced in many advanced cancers. Tarcic et al. report that downregulation of RNF20 and H2Bub1 promotes chronic colonic inflammation and inflammation-associated colorectal cancer in mice and humans, partly by augmenting NF-kB activity and attenuating the antitumoral T cell response.