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A role for GATA-2 in transition to an aggressive phenotype in prostate cancer through modulation of key androgen-regulated genes

Abstract

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 5α-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.

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Acknowledgements

This work is supported by grants from the Cancer Institute NSW, the National Health and Medical Research Council, the Prostate Cancer Foundation of Australia and the RT Hall Trust. We thank Professor Liz Musgrove, Dr Ross Laybutt and Dr Liz Caldon for helpful discussion and critical reading of the paper. Furthermore, we thank Ruth PeBenito for technical support.

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Correspondence to S M Henshall.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Böhm, M., Locke, W., Sutherland, R. et al. A role for GATA-2 in transition to an aggressive phenotype in prostate cancer through modulation of key androgen-regulated genes. Oncogene 28, 3847–3856 (2009). https://doi.org/10.1038/onc.2009.243

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  • DOI: https://doi.org/10.1038/onc.2009.243

Keywords

  • AR
  • GATA-2
  • prostate cancer
  • progression

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