Abstract
CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPβ isoforms while re-expression of EWS-FLI1 rescued C/EBPβ expression. Overexpression of C/EBPβ-1, the largest of the three C/EBPβ isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPβ decreased colony formation, and re-expression of either C/EBPβ-1 or C/EBPβ-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPβ in Ewing sarcoma. Furthermore, increased expression of C/EBPβ led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPβ-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance.
Highlights
Ewing sarcoma is the second most common bone cancer in children and young adults
To determine if C/EBPβ is expressed in Ewing sarcoma cells, we interrogated the Broad Institute’s Cancer Cell Line Encyclopedia (CCLE) [30] for expression of CCAAT/enhancer binding protein beta (CEBPB)
To explore the function of C/EBPβ isoforms in Ewing sarcoma, we overexpressed each of the three C/EBPβ isoforms in Ewing sarcoma cell lines
Summary
While the cell of origin is not known, histologically it is comprised of characteristic small round blue cells. This disease has a poor outcome, with a 60% survival rate for localized disease and less than 20% survival for metastatic disease [1, 2]. Ewing sarcoma is defined by a translocation of the EWSR1 gene to one of the ETS transcription factor family members, most commonly FLI1. This t(11;22) translocation encodes a fusion protein that acts as an oncogene by aberrantly transcribing genes involved in cellular proliferation and transformation [3, 4]. Investigation into the function of EWS-FLI1 target genes may help to identify disease risk factors and to develop novel treatments for Ewing sarcoma [7, 8]
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