Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10 D, Turku, Finland.
Institute of Biomedicine, University of Turku, Turku, Finland.
Sci Rep. 2023 Mar 25;13(1):4884. doi: 10.1038/s41598-023-31576-x.
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.
EWSR1::CREM 融合基因，由染色体易位 t(10;22)(p11;q12)引起，已在从低度恶性到高度恶性癌症的各种不同恶性肿瘤中被发现。易位产生嵌合蛋白 EWSR1::CREM。EWSR1::CREM 蛋白致癌特性背后的分子机制以前没有被系统地描述过。在这项研究中，我们使用 siRNA 介导的敲低，对黑色素瘤细胞系 CHL-1 进行了转录谱分析，以耗尽内源性 EWSR1::CREM 蛋白。我们发现 712 个基因的表达发生了改变（Log2 倍数变化≥2）。我们进行了途径分析，以确定 EWSR1::CREM 介导的途径，并进行了细胞研究，以检查敲低带来的功能差异。改变的途径涉及细胞周期和增殖，这在细胞迁移也受到影响的细胞研究中得到了进一步验证。在表达下调最大的靶基因中，我们发现了 ODC1——一种已被确立的致癌酶，它可以被药理学抑制，并且是多胺合成所必需的。我们发现，通过直接沉默 ODC1 的表达，也可以重现 EWSR1::CREM 敲低的主要作用。这些发现为携带 EWSR1::CREM 融合基因的肿瘤的发病机制提供了新的见解，有望促进新的治疗策略的发展。
