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

Ohad Tarcic1, Ioannis S Pateras2, Tomer Cooks1

  • 1Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 7610001, Israel.

Cell Reports
|February 9, 2016
PubMed

Insights

The E3 ubiquitin ligase RNF20/RNF40 and histone H2Bub1 regulate inflammation and cancer. Their downregulation promotes inflammation-associated colorectal cancer by altering NF-κB activity and immune cell populations.

Area of Science:

  • Molecular Biology
  • Oncology
  • Immunology

Background:

  • The link between inflammation and cancer is a significant area of research.
  • Chromatin regulation plays a crucial role in cellular processes, including inflammation and cancer development.

Purpose of the Study:

  • To investigate the role of the E3 ubiquitin ligase RNF20/RNF40 and histone H2B monoubiquitylation (H2Bub1) in inflammation and associated cancers.
  • To elucidate the molecular mechanisms by which RNF20/RNF40 and H2Bub1 influence inflammation-associated gene expression and immune responses.

Main Methods:

  • Utilized mouse models (RNF20(+/-) mice) and human patient samples (ulcerative colitis, colorectal tumors).
  • Assessed the expression of RNF20/RNF40, H2Bub1, and NF-κB components (p65, p50).
  • Analyzed heterochromatin marks (H3K9me3) and myeloid-derived suppressor cells (MDSCs).

Main Results:

  • Downregulation of RNF20 and H2Bub1 promotes NF-κB activation by favoring p65 dimers over p50 homodimers.
  • Reduced H2Bub1 leads to decreased H3K9me3 on NF-κB target genes, increasing their transcription.
  • RNF20(+/-) mice exhibit increased susceptibility to colonic inflammation and colorectal cancer, with elevated MDSCs.
  • Human ulcerative colitis and colorectal tumors show decreased RNF20/RNF40 and H2Bub1 in epithelial and stromal cells.

Conclusions:

  • RNF20/RNF40-mediated H2Bub1 is a critical modulator of inflammation and inflammation-associated cancer.
  • The findings highlight the clinical relevance of RNF20/RNF40 and H2Bub1 in human inflammatory bowel disease and colorectal cancer.

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