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Cancer Res. 2015 May 15;75(10):1992-2004. doi: 10.1158/0008-5472.CAN-14-0611. Epub 2015 Mar 13.

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

Author information

1
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
2
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China. richard.pestell@jefferson.edu kmwu2005@gmail.com.
3
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
4
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
5
Neural Stem Cell Institute, Rensselaer, New York.
6
Departments of Pathology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
7
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation. richard.pestell@jefferson.edu kmwu2005@gmail.com.

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.

PMID:
25769723
PMCID:
PMC4433595
DOI:
10.1158/0008-5472.CAN-14-0611
[Indexed for MEDLINE]
Free PMC Article

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