Project Summary Prostate cancer is amongst the most prevalent causes of death in the US. As such, despite great progress in our understanding of this disease, there still remains a dire need to explore the molecular mechanisms involved in prostate tumorigenesis that will ultimately help to improve detecting, preventing, confining and curing this disease. The discovery of recurrent chromosomal translocations in the majority of prostate tumors has uncovered a long sought-after cause of this cancer: the overexpression of ETS transcription factors, including ETV1. Our preliminary data demonstrate that posttranslational modification of ETV1 by SUMO represses its activity, suggesting one explanation how the observed overexpression of a SUMO protease aggravates prostate tumor formation. Moreover, we discovered that ETV1 cooperates with the histone demethylase JMJD2A, which itself is overexpressed in prostate tumors and induces the formation of high-grade prostatic intraepithelial neoplasia in our transgenic mouse model. Finally, we identified novel ETV1 target genes, whose dysregulation is likely to contribute to tumor formation. We hypothesize that ETV1 as well as JMJD2A can induce prostate tumor formation and may cooperate to do so. Further, we hypothesize that sumoylation of ETV1 crucially affects its oncogenic potential and that ETV1's ability to induce prostatic lesions is dependent on selected cancer-critical target genes. To test these hypotheses, we propose three specific aims of research: (i) To reveal how sumoylation affects the function of ETV1 at the molecular, cellular and organismal level. (ii) To determine how JMJD2A initiates prostate tumor formation and cooperates with ETV1. (iii) To define the role of selected, prostate-relevant target genes for ETV1's oncogenic activities. Our study will provide mechanistic insight into the roles of ETV1 and JMJD2A in the neoplastic transformation of prostate cells. Not in the least, our research may uncover that JMJD2A is an oncoprotein in its own right and cooperates with ETV1 during prostate tumorigenesis. The knowledge gained from these studies will enhance our understanding of prostate cancer pathophysiology and may point out several novel targets of therapeutic intervention, including SUMO proteases, JMJD2A and cancer-critical ETV1 target genes. In particular the fact that JMJD2A is an enzyme suggests that small molecule drugs can be developed that obstruct the function of this histone demethylase and thereby combat prostate cancer.

R01CA154745

2011-07-01

2017-04-30