Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma

Ewing Sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TKs) and associated pathways are continuously activated in many malignancies including EWS; these enzymes provide candidate therapeutic targets. Using two high-throughput screens with EWS cell lines (a siRNA library and a small-molecule inhibitor library of that predominantly target the TK family), we identified spleen tyrosine kinase (SYK) as a candidate actionable target. SYK is highly phosphorylated in the majority of EWS cells, and SYK inhibition by a variety of genetic and pharmacological approaches markedly inhibited EWS cells both in vitro and in vivo. Ectopic expression of SYK rescued the cytotoxicity triggered by SYK-depletion associated with the reactivation of AKT and c-MYC. Transcriptome analysis identified that a Long non-coding RNA, metastasis associated lung adenocarcinoma transcript 1 (MALAT1), was dependent on by SYK-mediated signaling. Moreover, c-MYC, a SYK up-regulated gene, bound to the promoter region of MALAT1 and transcriptional activated MALAT1, which further promoted the proliferation of EWS cells. Taken together, the present study identifies a novel signaling involving SYK/c-MYC/MALAT1 as a promising therapeutic target for the treatment of EWS.

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