Loss of the tumor suppressor PTEN is a common occurrence in prostate cancer.
This aberration leads to the ectopic activation of the PI3K-Akt pathway, which promotes tumor growth. Here, we show that the transcription factor Gata3 is progressively lost in Pten-deficient mouse prostate tumors as a result of both transcriptional down-regulation and increased proteasomal degradation. To determine the significance of this loss, we used conditional loss- and gain-of-function approaches to manipulate Gata3 expression levels in prostate tumors. Our results show that Gata3 inactivation in Pten-deficient prostates accelerates tumor invasion. Conversely, enforced expression of GATA3 in Pten-deficient tissues markedly delays tumor progression. In Pten-deficient prostatic ducts, enforced GATA3 prevented Akt activation, which correlated with the down-regulation of Pik3cg and Pik3c2a mRNAs, encoding respectively class I and II PI3K subunits. Remarkably, the majority of human prostate tumors similarly show loss of active GATA3 as they progress to the aggressive castrate-resistant stage. In addition, GATA3 expression levels in hormone-sensitive tumors holds predictive value for tumor recurrence. Together, these data establish Gata3 as an important regulator of prostate cancer progression.
Written by:
Nguyen AH, Tremblay M, Haigh K, Koumakpayi IH, Paquet M, Pandolfi PP, Mes-Masson AM, Saad F, Haigh JJ, Bouchard M. Are you the author?
Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3A 1A3.
Reference: Hum Mol Genet. 2013 Mar 6. Epub ahead of print.
doi: 10.1093/hmg/ddt088
PubMed Abstract
PMID: 23428429
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