# Pathogenic Roles of RNA-Binding Proteins in Sarcomas
## 3 Role of RBPs in Sarcomas
### Ewing Sarcoma  
Ewing sarcoma is a highly aggressive type of sarcoma, mostly affecting children. The 5 year overall survival is 70% in localized cases with intensive multidisciplinary treatment and 15-30% in advanced cases [62]. Standard therapy for advanced cases has not yet been established. Ewing sarcoma is molecularly characterized by an oncogenic chimeric aberrant transcription factor arising from a chromosome translocation, which fuses the transactivation (TAD) domain of EWS RNA-binding protein 1 (EWSR1) to the DNA-binding domain of ETS family genes [63]. Among the diverse ETS family genes, FLI1 is the most common fusion partner, accounting for 80-90% cases of Ewing sarcoma [63]. Given the fact that only 20% of Ewing sarcoma cases are accompanied by additional gene mutation, the aberrant transcription factor may have the ability to solely drive tumor phenotype [64]. EWS is a member of the TET family of RBPs and participates in the diverse aspects of RNA metabolism to regulate DNA repair, cell proliferation, senescence, etc. [65]. In addition to these functions on RNA processing, the role of TAD in EWS containing low-complexity sequence domains (LADs) has recently been shown to facilitate liquid-liquid phase transition [66]. [PERSON] et al. discovered that the presence of TAD is crucial for segregating EWS/FLI1 on its binding sites on the DNA sequence. The optimum concentrations of EWS/FLI1 and wildtype EWS in liquid-liquid phase transition are regulated within a narrow range to enhance the oncogenic transcription programs driven by EWS/FLI1. In addition, the TAD of EWS possesses prion-like domains, through which EWS interacts with the SWI/SNF complex, as well as RNA polymerase II. EWS/FLI1 establishes super-enhancers by recruiting the SWI/SNF complex to the target genes and dramatically increases transcriptional activity [67; 68; 69; 70]. To summarize, the phase separation model may explain the mechanisms of super-enhancer formation mediated by combined EWS/FLI1, SWI/SNF complex and RNA polymerase II. Recently, [PERSON] et al. discovered that some genes are uniquely transcribed by chimeric transcription factors, and their distinct transcription, mRNA processing, and translational pattern generates tumor neoantigens in oncogenic chimeric protein-driven sarcomas including Ewing sarcoma [71]. This fusion gene-mediated dysregulation on these molecular consequences leads to survival advantage of sarcomas. For example, ARID1A, a subunit of the SWI/SNF complex, is transcribed into several isoforms. EWS/FLI1 preferentially increases the ARID1A-L isoform over the ARID1A-S isoform. EWS/FLI1 directly interacts with the SWI/SNF complex through ARID1A-L and regulates target gene expression, resulting in promoting tumor growth (Figure 2) [72]. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Sarcoma** & **RNA Binding Proteins** & **T-Statistic** & _p-Value_ \\ \hline \multirow{3}{*}{Ewing sarcoma} & EWSR1 & \(-\)13.16812526 & 1.03 \(\times\) 10\({}^{-36}\) \\  & IGF2 BP1 & \(-\)12.2904187 & 1.70 \(\times\) 10\({}^{-32}\) \\  & STAG1 & \(-\)11.52248821 & 5.57 \(\times\) 10\({}^{-29}\) \\ \hline \multirow{2}{*}{Rhabdomyosarcoma} & QKI & \(-\)8.65279311 & 2.29 \(\times\) 10\({}^{-17}\) \\ \hline \multirow{2}{*}{Synovial sarcoma} & SRSF2 & \(-\)5.668685512 & 2.09 \(\times\) 10\({}^{-8}\) \\  & LSM14B & \(-\)4.679259416 & 3.26 \(\times\) 10\({}^{-6}\) \\ \hline \multirow{2}{*}{Osteosarcoma} & SUB1 & \(-\)5.501544322 & 4.92 \(\times\) 10\({}^{-8}\) \\  & ASCC3 & \(-\)4.133181793 & 3.91 \(\times\) 10\({}^{-5}\) \\ \hline \multirow{2}{*}{Liposarcoma} & DAZAP1 & \(-\)5.33256277 & 1.19 \(\times\) 10\({}^{-7}\) \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Top-ranked RNA-binding proteins (RBPs) in sarcomas according to the DepMap project. Some other well-known RBPs also contribute to the Ewing sarcoma pathogenesis. The LIN28 paralog is canonically known to regulate gene expression through let-7 miRNA family biogenesis. [PERSON] et al. discovered that LIN28B is highly expressed in a subset of Ewing sarcoma [73].