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Cell Rep. 2016 Feb 16;14(6):1462-1476. doi: 10.1016/j.celrep.2016.01.020. Epub 2016 Feb 4.

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

Author information

1
Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 7610001, Israel.
2
Molecular Carcinogenesis Group, Department of Histology-Embryology, School of Medicine, University of Athens, 11527 Athens, Greece.
3
The Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.
4
Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem 91120, Israel.
5
Department of Biological Services, Weizmann Institute of Science, Rehovot 7610001, Israel.
6
Department of Immunology and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Pathology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
7
Molecular Carcinogenesis Group, Department of Histology-Embryology, School of Medicine, University of Athens, 11527 Athens, Greece; Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece; Faculty Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
8
Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 7610001, Israel. Electronic address: moshe.oren@weizmann.ac.il.

Abstract

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.

PMID:
26854224
PMCID:
PMC4761112
DOI:
10.1016/j.celrep.2016.01.020
[Indexed for MEDLINE]
Free PMC Article

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