Abstract 1278: Elucidating the mechanistic role of ERG in prostate cancer

Abstract

Abstract Introduction: The transcription factor ERG is important for the development of angiogenesis, blood vessel integrity, and maintenance of hematopoietic stem cells. However, aberrant overexpression of ERG has been shown to be associated with various cancers. For example, ERG is recurrently involved in a translocation with TMPRSS2, which shifts it under AR regulation, and is thus subjected to overexpression in about 50% of prostate cancers in Caucasian males. While the clinical prognostic value of the TMPRSS2:ERG fusion is still debated, mechanistic studies of ERG-positive prostate cancers have demonstrated that ERG promotes cell invasion and metastasis. However, the molecular and cellular mechanisms of oncogenic ERG function in prostate cancer remain largely unclear. Methods/Results: To more comprehensively study the molecular and phenotypic roles of the TMPRSS2:ERG fusion product in prostate cancer, we developed an inducible ERG overexpression model in multiple cell lines as well as a CRISPR-Cas9-mediated TMPRSS2:ERG fusion translocation model. Using these models, we first performed RNA-seq and observed that ERG overexpression induced a global transcriptional program that increased the expression of genes related to epithelial-mesenchymal transition and decreased the expression of genes related to cell-cycle promotion. Further, using Boyden Chamber Assays as well as IncuCyte, we showed that overexpression of ERG promoted cell invasion but suppressed cell proliferation. We then used flow cytometric analysis to show that cells overexpressing ERG undergo a prolonged S phase. Interestingly, ERG antagonization through peptidomimetic inhibition partially rescued the proliferation rates of these ERG-overexpressing cells. Finally, using genome-wide CRISPR/Cas9 screening and NGS of the integrated sgRNA expression cassettes in the inducible ERG model, we identified panels of genes mediating ERG functions. Discussion: Unlike oncogenic kinases such as BCR-ABL in Chronic Myeloid Leukemia, transcription factors such as ERG have been more challenging to directly target in cancer. Thus, elucidation of the mechanisms of ERG-mediated transcriptional reprogramming, ERG binding partners, as well as the regulation of ERG, may result in the development of new strategies to target ERG by selectively antagonizing ERG oncogenic functions. Using our models, we are able to gain a better understanding of the role of ERG in cancer development and progression and thus provide insight for the development of new strategies for the prevention, detection, and treatment of prostate cancer. Citation Format: Caleb Cheng, Lanbo Xiao, Jean Tien, Cynthia Wang, Jesse Cheng, Eileen Shiau, Xiaoju Wang, Arul M. Chinnaiyan. Elucidating the mechanistic role of ERG in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1278.