The cell fate determination factor dachshund inhibits androgen receptor signaling and prostate cancer cellular growth.

Abstract	Initially isolated as the dominant suppressor of the mutant epidermal growth factor receptor (ellipse), the Dachshund gene plays a key role in metazoan development regulating the Retinal Determination Gene Network. Herein, the DACH1 gene was expressed in normal prostate epithelial cells with reduced expression in human prostate cancer. DACH1 inhibited prostate cancer cellular DNA synthesis, growth in colony forming assays, and blocked contact-independent growth in soft agar assays. DACH1 inhibited androgen receptor (AR) activity, requiring a conserved DS Domain (Dachshund domain conserved with Ski/Sno) that bound NCoR/HDAC and was recruited to an androgen-responsive gene promoter. DACH1 inhibited ligand-dependent activity of AR mutations identified in patients with androgen-insensitive prostate cancer. The DS domain was sufficient for repression of the AR wild-type but failed to repress an AR acetylation site point mutant. These studies show a role for the Retinal Determination Gene Network in regulating cellular growth and signaling in prostate cancer.
Authors	Kongming Wu, Sanjay Katiyar, Agnes Witkiewicz, Anping Li, Peter McCue, Liang-Nian Song, Lifeng Tian, Ming Jin, Richard G Pestell
Journal	Cancer research (Cancer Res) Vol. 69 Issue 8 Pg. 3347-55 (Apr 15 2009) ISSN: 1538-7445 [Electronic] United States
PMID	19351840 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Androgen Receptor Antagonists DACH1 protein, human Eye Proteins RNA, Messenger Receptors, Androgen Repressor Proteins Transcription Factors Dihydrotestosterone SIRT1 protein, human Sirtuin 1 Sirtuins Histone Deacetylases
Topics	Acetylation Androgen Receptor Antagonists Cell Growth Processes (physiology) Cell Line, Tumor Dihydrotestosterone (pharmacology) Eye Proteins (biosynthesis, genetics) Histone Deacetylases (metabolism) Humans Immunohistochemistry Male Prostatic Neoplasms (genetics, metabolism, pathology) Protein Structure, Tertiary RNA, Messenger (biosynthesis, genetics) Receptors, Androgen (genetics, metabolism) Repressor Proteins (metabolism) Signal Transduction Sirtuin 1 Sirtuins (metabolism) Transcription Factors (biosynthesis, genetics) Transcription, Genetic Transfection

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