Circuitous Ways of EWS::FLI1: Using Circular RNA ZNF609 to Evade Translational Repression by miR-145 in Ewing’s SARCOMA

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Abstract
Ewing’s sarcoma (EwS) is a pediatric bone and soft tissue cancer driven by the oncogenic fusion protein EWS::FLI1, with no current targeted therapies. Although the role of some of the non-coding RNAs (ncRNAs) including microRNAs and long non coding RNAs have been explored in EwS, no work is reported on presence and role of newly appreciated class of regulatory RNAs called circular RNAs (circRNA). Our work here reports the first identification and functional characterization of the role of circRNA circZNF609 in EwS. Here we identify and characterize circZNF609, a circRNA expressed in an EWS::FLI1-dependent manner, which promotes EwS cell proliferation, metastasis, and inhibits apoptosis. Mechanistically, circZNF609 acts as a sponge for miR-145-5p, preventing miRNA-mediated translational repression of EWS::FLI1, thereby sustaining oncogenic signaling. Inhibition of miR-145-5p partially rescues the effects of circZNF609 knockdown, confirming this regulatory axis. These findings reveal circZNF609 as a novel post-transcriptional regulator of EWS::FLI1 and suggest its potential as a therapeutic target in EwS.

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