TRIM27 mediates STAT3 activation at retromer-positive structures to promote colitis and colitis-associated carcinogenesis.

Abstract

STAT3 is a transcription factor that plays central roles in various physiological processes and its deregulation results in serious diseases including cancer. The mechanisms on how STAT3 activity is regulated remains enigmatic. Here we identify TRIM27 as a positive regulator of II-6-induced STAT3 activation and downstream gene expression. TRIM27 localizes to retromer-positive punctate structures and serves as a critical link for recruiting gp130, JAK1, and STAT3 to and subsequent phosphorylation of STAT3 at the retromer-positive structures. Overexpression of TRIM27 promotes cancer cell growth in vitro and tumor growth in nude mice, whereas knockdown of TRIM27 has opposite effects. Deficiency of TRIM27 significantly impairs dextran sulfate sodium (DSS)-induced STAT3 activation, inflammatory cytokine expression and colitis as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer in mice. These findings reveal a retromer-dependent mechanism for regulation of STAT3 activation, inflammation, and inflammation-associated cancer development.

• Authors: Hong-Xia Zhang, Zhi-Sheng Xu, Hen Lin, Mi Li, Tian Xia, Kaisa Cui, Su-Yun Wang, Youjun Li, Hong-Bing Shu, Yan-Yi Wang
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 3441 (08 24 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30143645 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Interleukin-6
• Nuclear Proteins
• STAT3 Transcription Factor
• TRIM27 protein, human
• Dextran Sulfate
• Trim27 protein, mouse
• Ubiquitin-Protein Ligases
• Azoxymethane

Topics

• Animals
• Azoxymethane (toxicity)
• Carcinogenesis (metabolism, pathology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (metabolism, pathology)
• Colitis (chemically induced, metabolism, pathology)
• DNA-Binding Proteins (genetics, metabolism)
• Dextran Sulfate (toxicity)
• HEK293 Cells
• HT29 Cells
• HeLa Cells
• Humans
• Interleukin-6 (pharmacology)
• Mice
• Nuclear Proteins (genetics, metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects, physiology)
• Ubiquitin-Protein Ligases