Editors' ChoiceCancer

TMPRSS2-ERG, a Mover and a Shaker

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Science Translational Medicine  02 Jun 2010:
Vol. 2, Issue 34, pp. 34ec86
DOI: 10.1126/scitranslmed.3001313

In 2005, Tomlins et al. found that a translocation juxtaposing the TMPRSS2 target gene of the androgen receptor (AR), the central pathway in prostate cancer, to the ETS transcription factor, ERG, is a common event in prostate cancer. Consequently, AR drives expression of the TMPRSS2-ERG fusion. Transgenic mouse models demonstrate that ERG is an oncogene. However, it was not clear how ERG mediates transformation.

Using an integrative genomics approach, which included massive parallel sequencing after chromatin immunoprecipitation (ChIP), expression microarrays, and bioinformatics, Yu et al. now shed light on ERG’s role in prostate cancer. Unexpectedly, they found that ERG colocalizes with AR at many genomic sites. Surprisingly, ERG attenuates expression of AR-bound genes, which are involved in AR’s pro-differentiation program. Additionally, ERG directly binds to the AR promoter and represses AR’s expression, and in localized human prostate cancer samples ERG and AR expression were inversely correlated. Although this might seem paradoxical because AR drives expression of TMPRSS2-ERG, it is possible that TMPRSS2-ERG serves as a rheostat of AR function rather than an on/off switch. Additionally, in metastatic prostate cancer samples the presence of the TMPRSS2-ERG fusion was found to correlate with higher expression of AR. This raises the question of whether AR gene amplification, which promotes persistent AR expression and is a common mechanism of resistance to androgen-deprivation therapy, may be selected for in metastasis because of TMPRSS2-ERG.

Finally, Yu et al. also demonstrated that ERG has a critical role in the function of the polvcomb protein EZH2, which is upregulated in prostate cancer and was recently shown to promote prostate cancer metastasis. ERG binds to the EZH2 promoter and activates its expression. ERG also interacts with EZH2 to repress expression of pro-differentiation genes, including AR targets. This leads to a de-differentiated transcriptional program, not dissimilar from embryonic stem cells.

This work links ERG’s oncogenic effects to critical pathways in prostate cancer: AR and polycomb. Therapies that target ERG do not currently exist, but once they are developed, mechanism-based clinical trials will be necessary to determine whether the balance of ERG inhibition is favorable or unfavorable (given ERG’s inhibitory effects on AR signaling). However, this report clearly indicates why this concept is worthy of further testing.

J Yu et al., An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell. 17, 443–454 (2010). [Abstract]

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