# Pathogenic Roles of RNA-Binding Proteins in Sarcomas
## 1 Introduction  
RNA-binding proteins (RBPs) are involved in multiple steps of RNA metabolism including RNA splicing, polyadenlation, transport, maintenance of RNA stability and degradation, intracellular localization, and translation control. There is an increasing amount of evidence that alterations in the expression or activity of RBPs can lead to a variety of disorders including cancers and sarcomas. Defining the network of interactions between RBPs and disease-associated RNA targets will contribute to a better understanding of tumor pathology and a development of novel therapeutic agents.  
RBPs generally have conserved domains and common sequences that interact with RNA and other proteins to form ribonucleoprotein (RNP) complexes. RBPs determine the fate of target RNAs by recruiting a variety of proteins and other cellular components [1]. RBPs were originally identified for their ability to bind various types of RNA through the formation of stable RNA-binding domains (RBDDs) of one or more secondary and tertiary structures, which in turn affect gene expression. Currently, approximately 50 differentRBDs have been identified to classify RBPs. Classical RBDs include K homologous domain (KH), RNA recognition motif (RRM), zinc finger domain (ZNF), Pumilio homologous domain (PUM), and double-stranded RNA-binding domain (dsRBD) [2]. Interestingly, only one-quarter of these RBPs contain classical RBDs while the remainder contain non-standard RBDs with previously uncharacterized motifs [3]. Other unconventional RBPs, which lack recognizable RBDs but typically contain intrinsically disordered regions or mononucleotide- and dinucleotide-binding domains directly involved in RNA binding, are known as \"enigma RBPs\" because the known cellular biological functions of these proteins are unrelated to RNA biology [4]. The combination of the versatility and structural flexibility of RBDs enables RBPs to control the metabolism of many transcripts. RBPs play a critical role in the regulation of gene expression through post-transcriptional regulation such as alternative splicing, selective polyadenylation, subcellular localization, stability, and RNA translation, as we review later [5; 6].  
Recent intensive genomic sequencing studies in malignant disorders have revealed recurrent mutations and aberrant activation and deactivation of RBPs due to both genetic and nongenetic factors, suggesting essential roles of RBPs in the initiation and progression of tumors. In addition, advanced technologies assessing RNA-protein interactions have identified more than 4000 proteins as potential RBPs. These advances associated with RBPs and RNA have greatly enhanced basic and translational research on how these RBPs contribute to tumorigenesis.  
In fact, it is now clear that RBPs are dysregulated in several types of cancer, thereby affecting the expression and function of oncoprotein and/or tumor suppressor proteins [7; 8]. Clinicopathological and immunohistochemical studies of cancer cases have shown that some RBPs are abnormally expressed in cancer relative to the surrounding normal tissues, and such aberrant expression is correlated with the prognosis of patients [9; 10; 11]. For example, [PERSON] et al. identified RBM39 as a differentially expressed RBPs in acute myeloid leukemia (AML) compared with normal human CD34+ hematopoietic stem and progenitor cells [12]. A domain-focused CRISPR/Cas9 screen uncovered a network of interacting RBPs in AML that are essential for RNA splicing and AML survival including RBM39, which can be targeted by sulfonamides (including indisulium (also known as E7070), E7820, and chloroquinealine sulfonamide) [12; 13].  
On the basis of recent advances in the understanding of RBPs in the pathogenesis of malignant tumors, we provide a concise review of RBPs covering their functional roles in RNA metabolism and dysregulation in sarcomas.