The Landscape of Regulatory Noncoding RNAs in Ewing's Sarcoma

Abstract

Ewing's sarcoma (ES) is a pediatric sarcoma caused by a chromosomal translocation. Unlike in most cancers, the genomes of ES patients are very stable. The translocation product of the EWS-FLI1 fusion is most often the predominant genetic driver of oncogenesis, and it is pertinent to explore the role of epigenetic alterations in the onset and progression of ES. Several types of noncoding RNAs, primarily microRNAs and long noncoding RNAs, are key epigenetic regulators that have been shown to play critical roles in various cancers. The functions of these epigenetic regulators are just beginning to be appreciated in ES. Here, we performed a comprehensive literature review to identify these noncoding RNAs. We identified clinically relevant tumor suppressor microRNAs, tumor promoter microRNAs and long noncoding RNAs. We then explored the known interplay between different classes of noncoding RNAs and described the currently unmet need for expanding the noncoding RNA repertoire of ES. We concluded the review with a discussion of epigenetic regulation of ES via regulatory noncoding RNAs. These noncoding RNAs provide new avenues of exploration to develop better therapeutics and identify novel biomarkers.

Keywords: Ewing’s sarcoma; biomarkers; epigenetics; long noncoding RNAs; microRNAs; noncoding RNAs; regulatory RNAs; therapeutic targets; tumor progression.

Figure 1

Noncoding RNAs and ES. (a) A chimeric fusion product of EWS and FLI1 genes, EWS-FLI1, exerts epigenetic control by regulating the expression of different classes of ncRNAs (shown as blue arrows). (b) Some ncRNAs also alter the expression of EWSFLI1 as a means of feedback regulation of their own expression levels. (c) ncRNAs have an extensive interplay between each other (shown as red arrows). (d) ncRNAs play roles in regulating transcription, RNA export and transport. They interact with different RNA binding proteins (RBPs), translation and modulating signaling pathways. Red question marks indicate unknown and yet to be explored connections.

Figure 2

Potential link between miRNAs identified in other cancers. (A) miR-let7f acts as a tumor suppressor miRNA by downregulating the oncogene Aurora B kinase in osteosarcoma. (B) miR-9-3p acts as an oncogenic miRNA by suppressing BLCAP which is required for inducing apoptosis in thyroid cancer. Both of these target genes are similarly affected in ES, but the role of these miRNAs is not yet elucidated in ES. The solid arrows indicate known pathways, the dotted arrows indicate yet to be explored pathways.