Genome-wide identification of IGF2BP3-targeted mRNA degradation reveals the functional linkage of two proto-oncogenes IGF2BP3 and EIF4E. Homo sapiens

RNA-binding proteins (RBPs) play important roles in tumorigenesis. IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers. Although IGF2BP3 has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of information regarding IGF2BP3 target mRNAs. Here we report the identification of IGF2BP3 target mRNAs and IGF2BP3 function in cancer proliferation. We identified mRNAs with altered expression in IGF2BP3-depleted cells by massive sequencing analysis and IGF2BP3 binding RNAs by immunoprecipitation of IGF2BP3 followed by massive sequencing analysis, resulting in the identification of 110 candidates that are negatively regulated by IGF2BP3. We found that IGF2BP3 destabilized EIF4EBP2 and MEIS3 mRNAs. Co-immunoprecipitation analysis revealed the interaction between IGF2BP3 and ribonucleases such as XRN2 and exosome component. The retarded proliferation of IGF2BP3-depleted cells was partially rescued by the depletion of EIF4EBP2 which negatively regulates EIF4E, an activator of translation and a well-known proto-oncogene. Consistent with this observation, IGF2BP2 depletion reduced phosphorylated EIF4E, the active form, and translational efficiency of EIF4E target transcripts. Finally, we found an inverse correlation between the expression level of IGF2BP3 and EIF4EBP2 in human lung adenocarcinoma tissues. Together these results suggest that IGF2BP3 promotes EIF4E-mediated translational activation through the reduction of EIF4EBP2 via mRNA degradation, leading to enhanced cell proliferation. Namely, we found the first evidence of functional linkage between previously well-known cancer biomarker, IGF2BP3 and EIF4E. This is also the first report demonstrating that IGF2BP3 is an RNA destabilizing factor.