The cell fate Determination factor Dachshund inhibits androgen receptor signaling and prostate cancer cellular growth

Kongming Wu, Sanjay Katiyar, Agnes Witkiewlcz, Anping Li, Peter Mccue, Liang Nian Song, Lifeng Tian, Ming Jin, Richard G. Pestell

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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.

Original languageEnglish
Pages (from-to)3347-3355
Number of pages9
JournalCancer Research
Volume69
Issue number8
DOIs
StatePublished - Apr 15 2009
Externally publishedYes

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