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

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Ohad Tarcic, Ioannis S. Pateras, Tomer Cooks, Efrat Shema, Julia Kanterman, Hadas Ashkenazi, Hana Boocholez, Ayala Hubert, Ron Rotkopf, Michal Baniyash, Eli Pikarsky, Vassilis G. Gorgoulis, Moshe Oren
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

Teaser

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.


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