The Role and Mechanism of EYA3 Overexpression in Ewing's Sarcoma

Résumé du livre

"Ewing's sarcoma is a devastating pediatric cancer of the bone and soft tissues that carries an especially poor prognosis for patients with chemotherapy-resistant tumors and for patients who battle relapsing disease. In an effort to better understand the molecular mechanisms of Ewing's sarcoma chemoresistance, we became interested in a potential role for DNA repair proteins in Ewing's sarcoma. Our lab studies the SIX family of homeoproteins and their co-activators, the EYA family, and we set out to explore a role for EYA in Ewing's sarcoma because of its newly defined role in DNA repair, which is attributable to its phosphatase activity. We found EYA3 to be overexpressed in Ewing's sarcoma cell lines and human tumors compared with human mesenchymal stem cells, the presumptive cell of origin of Ewing's sarcoma, and hypothesized that because EYA3 has a role in DNA repair, that overexpression of this protein may contribute to resistance to DNA-damaging chemotherapeutics in this disease. We went on to show that indeed, inhibition of EYA3 in Ewing's sarcoma cell lines is able to sensitize Ewing's sarcoma cells to DNA-damaging chemotherapeutics commonly used in the treatment of Ewing's sarcoma patients through decreased DNA repair. Further, inhibition of EYA3 decreases baseline survival in these cells. Additionally, we defined the molecular mechanisms of EYA3 overexpression in Ewing's sarcoma. The fusion protein transcription factor, EWS/FLI1, that drives Ewing's sarcoma oncogenesis represses microRNA-708, which targets the EYA3 3'UTR, resulting in increased EYA3 expression in the presence of EWS/FLI1, and this mechanism holds true in human Ewing's sarcoma tumor samples. Further, our data suggest a possible role for EYA3 in tumor-initiation cell (TIC) population maintenance/expansion, which mechanistically may contribute to EYA3- mediated chemoresistance. Lastly, we test the in vitro efficacy of a novel EYA phosphatase inhibitor and demonstrate that this small molecule inhibitor is able to effectively inhibit EYA-dependent SIX1-mediated transcription, as a readout for its functionality within human cells. These data describe, for the first time, a role for EYA proteins in cancer cell chemoresistance and further characterize novel inhibitors of EYA, in an effort to one day improve treatment outcomes for pediatric patients suffering from Ewing's sarcoma"--Abstract.