Insulin-like growth factor 2 mRNA-binding protein 3 is a novel post-transcriptional regulator of Ewing sarcoma malignancy

Purpose: Large-scale sequencing studies have indicated that besides genomic alterations, the post-transcriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma (ES). We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of ES aggressiveness. Experimental Design: Explorative study was performed in 15 patients with localized ES using RNAseq. Next, 128 patients with localized ES were divided into two cohorts. In the training set, 29 ES samples were analyzed using Affymetrix GeneChip arrays. In the validation set, 99 ES samples were examined using qRT-PCR. Patient-derived cell lines and experimental models were used for functional studies.  Results: Univariate and multivariate analyses indicated IGF2BP3 as a potent indicator of poor prognosis. Furthermore, ABCF1 mRNA was identified as a novel partner of IGF2BP3. Functional studies indicated IGF2BP3 as an oncogenic driver and ABCF1 mRNA as a sponge that by binding IGF2BP3, partly repressed its functions. The combined evaluation of IGF2BP3 and ABCF1 could identify different patient outcomes-high IGF2BP3 and low ABCF1 levels indicated poor survival (25%), whereas low IGF2BP3 and high ABCF1 levels indicated favorable survival (85.5%). The bromodomain and extraterminal domain inhibitor (BETi) JQ1 decreased IGF2BP3 expression, modified the expression of its validated targets and inhibited the capability of ES cells to grow under anchorage-independent conditions.  Conclusions: The combined assessment of IGF2BP3 and ABCF1 predicts recurrence in ES patients. Thus, for patients with high expression of IGF2BP3 and poor probability of survival, the use of BETis should be clinically evaluated.

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