The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a cxcl signaling module.

Abstract

Prostate cancer is the second leading form of cancer-related death in men. In a subset of prostate cancer patients, increased chemokine signaling IL8 and IL6 correlates with castrate-resistant prostate cancer (CRPC). IL8 and IL6 are produced by prostate epithelial cells and promote prostate cancer cell invasion; however, the mechanisms restraining prostate epithelial cell cytokine secretion are poorly understood. Herein, the cell-fate determinant factor DACH1 inhibited CRPC tumor growth in mice. Using Dach1(fl/fl)/Probasin-Cre bitransgenic mice, we show IL8 and IL6 secretion was altered by approximately 1,000-fold by endogenous Dach1. Endogenous Dach1 is shown to serve as a key endogenous restraint to prostate epithelial cell growth and restrains migration via CXCL signaling. DACH1 inhibited expression, transcription, and secretion of the CXCL genes (IL8 and IL6) by binding to their promoter regulatory regions in chromatin. DACH1 is thus a newly defined determinant of benign and malignant prostate epithelium cellular growth, migration, and cytokine abundance in vivo.

• Authors: Ke Chen, Kongming Wu, Xuanmao Jiao, Liping Wang, Xiaoming Ju, Min Wang, Gabriele Di Sante, Shaohua Xu, Qiong Wang, Kevin Li, Xin Sun, Congwen Xu, Zhiping Li, Mathew C Casimiro, Adam Ertel, Sankar Addya, Peter A McCue, Michael P Lisanti, Chenguang Wang, Richard J Davis, Graeme Mardon, Richard G Pestell
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 10 Pg. 1992-2004 (May 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25769723 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Cytokines
• DACH1 protein, human
• Eye Proteins
• Protein Sorting Signals
• Transcription Factors

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cytokines (metabolism)
• Epithelial Cells (physiology)
• Eye Proteins (physiology)
• Humans
• Male
• Mice, Transgenic
• Neoplasm Transplantation
• Prostate (pathology)
• Prostatic Neoplasms (metabolism, pathology)
• Protein Sorting Signals
• Transcription Factors (physiology)