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, plays an essential role in hematopoiesis. Recent studies have indicated that GATA-2 is involved in the androgen receptor (AR) signaling cascade, however, little is known regarding the role of GATA-2 in prostate cancer. Here, we report an association of GATA-2 with prostate cancer recurrence. Using immunohistochemical analysis, we show that GATA-2 is expressed within the luminal epithelium of a substantial proportion of prostate cancers and that high expression of GATA-2, detected in 15% of prostate cancer patients, is associated with biochemical recurrence and distant metastatic progression in a validation set of 203 prostate cancers. In vitro data demonstrate that GATA-2 is directly recruited to the promoter region of the AR upon androgen stimulation of LNCaP prostate cancer cells with 5?-dihydroxytestosterone (DHT) for 24 hours. 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 the AR target gene KLK2, which increase further in a time-dependent manner upon 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 via modulation of expression of AR and key androgen-regulated genes, one of which, AZGP1, is associated with the progression to metastatic disease.
|Authors||Bohm, M.; Locke, W.; Sutherland, R.L.; Kench, J.G.; Henshall, S.M.;|
|Published Date||2009-11-01 00:00:00|