Abstract B37: EWS-ERG targets transcriptional co-factors in ERG-positive Ewing sarcoma.

Ewing sarcoma is a highly aggressive and malignant tumor that occurs in the bone or soft tissue. It affects children and adolescents with majority of incidence between the age of 10 and 20 and about 250 children and adolescents are diagnosed each year in US. There is a clear health disparity seen in Ewing sarcoma population. The overall survival rates for black and hispanic patients have shown to be significantly worse compared to white patients. Previously, Drs. Reddy and Rao have discovered ERG (ETS Related Gene) and several important members of ETS family genes and have shown that ERG gene encodes for sequence specific transcriptional activators. Ewing sarcoma is characterized by chromosomal translocations involving EWS gene and one of the ETS (Erythroblastosis virus E26 transformation–specific) families of transcription factors (ERG, FLI1, ETV1, ETV4, E1AF and FEV). Dr. Reddy's laboratory has demonstrated that EWS gene codes for RNA binding protein and the fusion protein (EWS-ERG) functions as transcriptional activator. Our results have shown that EWS-ERG also inhibits transcriptional activation properties of RXR. This suggests that the aberrant fusion protein (EWS-ERG) may target transcriptional co-factors and thereby regulate RXR transcriptional activity. To understand the molecular mechanism of action of how the fusion protein targets nuclear receptor function and to provide a clue for the cancer health disparity seen in Ewing Sarcoma, we hypothesized that the aberrant fusion protein EWS-ERG targets CBP and other members of the transcriptional machinery causing transcriptional repression of RXR activity. Methods: We propose to study the interaction of EWS-ERG and CBP by co-immunoprecipitation approach and also investigate whether this interaction has a role in the inhibition of RXR transcriptional activity by luciferase assays. Results: 1. EWS-ERG inhibits RXR transcriptional activity. 2. EWS-ERG interacts with CBP in Ewing Sarcoma cells. 3. Overexpression of dominant negative mutant of CBP relieves EWS-ERG inhibition of RXR transcriptional activity. Conclusion: The transcriptional co-factor (CBP) is sequestered by the aberrant fusion protein EWS-ERG which inhibits the binding of RXR with CBP and other members of the transcriptional machinery causing transcriptional repression of RXR activity. This study may provide a clue for the cancer health disparity seen in Ewing Sarcoma and may have a profound impact on prevention, management and treatment of many types of cancers. Citation Format: Shubhalaxmi P. Kayarthodi, Yasuo Fujimura, Kunchala Rungasrisuriyachai, Huali Xu, Jinbo Fang, Chunshu Yang, Veena N. Rao, E.Shyam P. Reddy. EWS-ERG targets transcriptional co-factors in ERG-positive Ewing sarcoma. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B37.