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.
Bibliographical noteFunding Information:
We thank Steven A. Johnsen for the kind gift of antibodies, Neil Perkins, Fiona Oakley, Intidhar Galy, and Ronny Drapkin for helpful suggestions and reagents, and Hagai Marmor, Nir Itzkovits, and Liad Margalit for help with experiments. This work was supported in part by grant 293438 (RUBICAN) from the European Research Council, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, a Center of Excellence grant (1779/11) from the Israel Science Foundation, a Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI), EC FP7 funding (INFLACARE, agreement 223151, and INSPiRE, agreement 284460), grant R37 CA40099 from the National Cancer Institute, and the Lower Saxony-Israeli Association. M.O. is incumbent of the Andre Lwoff Chair in Molecular Biology.
© 2016 The Authors.