A role for GATA-2 in transition to an aggressive phenotype in prostate cancer through modulation of key androgen-regulated genes.
GATA-2, a member of the GATA family of transcription factors, is involved in androgen receptor (AR) signaling, however, little is known regarding its role in prostate cancer. Here, we report that GATA-2 is expressed in a substantial proportion of prostate cancers and that high expression of GATA-2 is associated with biochemical recurrence and distant metastatic progression in a validation set of 203 cancers. In vitro data show that GATA-2 is directly recruited to the promoter region of the AR upon androgen stimulation of LNCaP prostate cancer cells with 5alpha-dihydroxytestosterone (DHT) for 24 h. Ectopic GATA-2 expression causes the induction of AR transcript levels under androgen-depleted conditions (P<0.05). The expression of the AR target gene, AZGP1, is induced upon androgen stimulation and this effect is repressed by GATA-2. In contrast, GATA-2 significantly increases transcript levels of KLK2, which increases further in a time-dependent manner on DHT treatment and in the presence of GATA-2. These results indicate that upregulation of GATA-2 may contribute to the progression to aggressive prostate cancer through modulation of expression of AR and key androgen-regulated genes, one of which, AZGP1, is associated with the progression to metastatic disease.
Böhm
M
M
Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
Locke
W J
WJ
Sutherland
R L
RL
Kench
J G
JG
Henshall
S M
SM
D054392:Adipokines; D002352:Carrier Proteins / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000032:analysis / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics; D020840:Tissue Kallikreins / Q000235:genetics; D000090203:Zn-Alpha-2-Glycoprotein
D054392:Adipokines; D002352:Carrier Proteins; D050989:GATA2 Transcription Factor; D006023:Glycoproteins; D011944:Receptors, Androgen; D020840:Tissue Kallikreins; C488891:AZGP1 protein, human; D000090203:Zn-Alpha-2-Glycoprotein; C494711:GATA2 protein, human