Ewing Sarcoma Protein: A Key Player in Human Cancer

The Ewing sarcoma protein (EWS) is a well-known player in cancer biology for the specific translocations occurring in sarcomas. The EWS-FLI1 gene fusion is the prototypical translocation that encodes the aberrant, chimeric transcription factor, which is a landmark of Ewing tumors. In all described Ewing sarcoma oncogenes, the EWS RNA binding domains are completely missing; thus RNA binding properties are not retained in the hybrid proteins. However, it is currently unknown whether the absence of EWS function in RNA metabolism plays a role in oncogenic transformation or if EWS plays a role by itself in cancer development besides its contribution to the translocation. In this regard, recent reports have highlighted an essential role for EWS in the regulation of DNA damage response (DDR), a process that counteracts genome stability and is often deregulated in cancer cells. The first part of this review will describe the structural features of EWS and its multiple roles in the regulation of gene expression, which are exerted by coordinating different steps in the synthesis and processing of pre-mRNAs. The second part will examine the role of EWS in the regulation of DDR- and cancer-related genes, with potential implications in cancer therapies. Finally, recent advances on the involvement of EWS in neuromuscular disorders will be discussed. Collectively, the information reviewed herein highlights the broad role of EWS in bridging different cellular processes and underlines the contribution of EWS to genome stability and proper cell-cycle progression in higher eukaryotic cells. 1. Introduction EWS was originally identified because of the t(ll;22) (q24;q12) chromosome translocation, characteristic of Ewing sarcoma and related subtypes of primitive neuroectodermal tumors [1]. In these types of cancers, a hybrid transcript is generated by the genomic regions where the breakpoints of chromosome 22 and 11 occur. The translocation alters the open reading frame of the EWSR1 gene on chromosome 22 by substituting a sequence encoding a putative RNA-binding domain with that of the DNA-binding domain of FLI-1, the human homologue of murine Fli-1 [2]. Another translocation involving the EWSR1 gene was subsequently identified in malignant melanoma of soft parts: the deduced chimaeric protein consisted of the N-terminal domain of EWS linked to the bZIP domain of ATF-1, a transcription factor regulated by cAMP that was not previously implicated in oncogenesis [3]. In addition to the EWS-FLI-1 and EWS-ATF-1 fusions, the EWSR1 gene can be fused to ERG, which encodes a