IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression hallmark in cancer [METTL KD in PANC-1 (polyA RNA)]

The IGF2 mRNA-binding protein 1 (IGF2BP1) is a post-transcriptional enhancer of tumor growth. However, conserved effector pathway(s) and the feasibility of targeting IGF2BP1 in cancer cells remained elusive. We demonstrate that IGF2BP1 is a conserved regulator of E2F-driven gene expression and cancer cell cycle progression. IGF2BP1 promotes positive regulators of G1/S transition by stabilizing the respective mRNAs. This regulation is 3'UTR-, miRNA- and m6A-dependent, suggesting a conserved role of m6A-enhanced cell cycle progression across cancers. IGF2BP1 stabilizes E2F-encoding mRNAs and some of their target transcripts revealing a post-transcriptional super-enhancer role of the protein in E2F-driven gene expression. The small molecule BTYNB disrupts this super-enhancer function by impairing IGF2BP1-RNA association and consequently interferes with tumor cell proliferation and tumor growth. Overall design: polyA RNA-Seq of PANC-1 cells transfected with either control siRNAs (siC) or siRNAs directed against METTL3 and METTL14. Three replicates per condition.