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

Ke Chen, Kongming Wu, Xuanmao Jiao, Liping Wang, Xiaoming Ju, Min Wang, Gabriele D. 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. DavisGraeme Mardon, Richard G. Pestell

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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 Dach1fl/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.

Original languageEnglish
Pages (from-to)1992-2004
Number of pages13
JournalCancer Research
Volume75
Issue number10
DOIs
Publication statusPublished - 15 May 2015
Externally publishedYes

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