The cell fate determination factor dachshund inhibits androgen receptor signaling and prostate cancer cellular growth.
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.
Wu
Kongming
K
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, Pennsylvania 19107, USA. Kongming.Wu@jefferson.edu
Katiyar
Sanjay
S
Witkiewicz
Agnes
A
Li
Anping
A
McCue
Peter
P
Song
Liang-Nian
LN
Tian
Lifeng
L
Jin
Ming
M
Pestell
Richard G
RG
D000107:Acetylation; D059002:Androgen Receptor Antagonists; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
D059002:Androgen Receptor Antagonists; C486747:DACH1 protein, human; D005136:Eye Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D012097:Repressor Proteins; D014157:Transcription Factors; D013196:Dihydrotestosterone; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases