title: 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.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ju
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Sante
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Kevin
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Congwen
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCue
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Neural Stem Cell Institute, Rensselaer, New York.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Departments of Pathology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Graeme
authors.initials: G
authors.lastname: Mardon
authors.affiliation: 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.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology*; D005136:Eye Proteins / Q000502:physiology*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D021382:Protein Sorting Signals; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D016207:Cytokines; C486747:DACH1 protein, human; D005136:Eye Proteins; D021382:Protein Sorting Signals; D014157:Transcription Factors