The oncogenic properties of the EWSR1::CREM fusion gene are associated with polyamine metabolism

Abstract

The EWSR1::CREM fusion gene, caused by a chromosomal translocation t(10;22)(p11;q12), has been discovered in divergent malignancies, ranging from low-grade to highly malignant cancers. The translocation gives rise to a chimeric protein, EWSR1::CREM. The molecular mechanisms behind the oncogenic properties of the EWSR1::CREM protein have not previously been systematically characterized. In this study, we performed transcriptional profiling of the melanoma cell line CHL-1, with depletion of endogenous EWSR1::CREM protein using siRNA mediated knockdown. We found that the expression of 712 genes was altered (Log2 fold-change ≥ 2). We performed pathway analysis to identify EWSR1::CREM mediated pathways and cell studies to examine functional differences brought upon by the knockdown. Altered pathways involved cell cycle and proliferation, this was further validated by the cell studies where cell migration was affected as well. Among the target genes with the greatest downregulation, we discovered ODC1—a well-established oncogenic enzyme that can be pharmacologically inhibited and is essential for polyamine synthesis. We found that the main effects seen upon EWSR1::CREM knockdown can be reproduced by directly silencing ODC1 expression. These findings provide novel insights into pathogenesis of tumors harboring a EWSR1::CREM fusion gene, hopefully facilitating the development of novel therapeutic strategies.