Functional role of Erg in prostate cancer

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Reddy and his colleagues have identified, cloned and characterized human erg (ets related gene) gene and shown that it codes for sequence specific transcriptional activators. Erg gene is involved in the Ewing family of tumors and human myeloid leukemias. Erg and aberrant erg proteins were shown to inhibit apoptosis suggesting that this anti-apoptotic function may play a role in transformation. Erg gene is also shown to be fused with the prostate specific androgen regulated gene, TMPRSS2 in a majority of human prostate cancers resulting in the over expression of erg. African-American men in the United States are affected by prostate cancer in a disproportionate number compared to White men. Therefore, studying the role of erg in Drostate cancer becomes important for developing future therapeutic strategies and in reducing health disparity seen among African-American males. It was observed that erg related protein, Fli-1 and EWS-Fli-1 target CBP like E1A onco-protein resulting in transformation. Thus, viral transforming proteins and fusion onco-proteins appear to follow a similar strategy for transformation of cells. Interestingly, we have observed erg proteins to bind CBP suggesting that they may target transcriptional co-activators (CBP/p300) in prostate cancer cells resulting in the deregulation of multiple signal transduction pathways including regulation of apoptosis. These observations suggest that over expressed erg proteins target CBP resulting in survival of prostate cancer cells leading to transformation. Therefore, we have hypothesized that high levels of erg may be competing for CBP resulting in inhibition of CBP-mediated transcriptional activation properties of Retinoid X receptors (RXR alpha). Since transcriptional activation properties of RXR alpha are essential for apoptosis, it is reasonable to hypothesize that erg may interfere with RXR alpha/CBP-mediated apoptosis. This hypothesis will be tested both in vitro and in vivo. These studies will not only explain the molecular mechanism of activation of erg gene in human prostate cancers but also provide clues for therapeutic intervention.