IGF2BP1 Promotes Proliferation of Neuroendocrine Neoplasms by Post-Transcriptional Enhancement of EZH2

SIMPLE SUMMARY: Neuroendocrine neoplasms (NEN) are very heterogeneous malignancies arising at different sites of the body that show an increasing incidence in recent decades. Here, we show that IGF2 mRNA binding protein 1 (IGF2BP1) is highly expressed in NEN cell lines, leading to enhanced cell proliferation. This oncogenic function relies on post-transcriptional stimulation of EZH2 expression by IGF2BP1, resulting in epigenetic silencing of cell cycle inhibitors via tri-methylation of histone H3 at lysine 27 (H3K27me3). Combinatorial pharmacological targeting of IGF2BP1, EZH2, and the EZH2-activator Myc leads to synergistic antiproliferative and proapoptotic effects in NEN cells, representing a novel therapeutic strategy in neuroendocrine malignancies. ABSTRACT: Neuroendocrine neoplasms (NENs) represent a heterogenous class of highly vascularized neoplasms that are increasing in prevalence and are predominantly diagnosed at a metastatic state. The molecular mechanisms leading to tumor initiation, metastasis, and chemoresistance are still under investigation. Hence, identification of novel therapeutic targets is of great interest. Here, we demonstrate that the RNA-binding Protein IGF2BP1 is a post-transcriptional regulator of components of the Polycomb repressive complex 2 (PRC2), an epigenic modifier affecting transcriptional regulation and proliferation: Comprehensive in silico analyses along with in vitro experiments showed that IGF2BP1 promotes neuroendocrine tumor cell proliferation by stabilizing the mRNA of Enhancer of Zeste 2 (EZH2), the catalytic subunit of PRC2, which represses gene expression by tri-methylation of histone H3 at lysine 27 (H3K27me3). The IGF2BP1-driven stabilization and protection of EZH2 mRNA is m6A-dependent and enhances EZH2 protein levels which stimulates cell cycle progression by silencing cell cycle arrest genes through enhanced H3K27 tri-methylation. Therapeutic inhibition of IGF2BP1 destabilizes EZH2 mRNA and results in a reduced cell proliferation, paralleled by an increase in G1 and sub-G1 phases. Combined targeting of IGF2BP1, EZH2, and Myc, a transcriptional activator of EZH2 and well-known target of IGF2BP1 cooperatively induces tumor cell apoptosis. Our data identify IGF2BP1 as an important driver of tumor progression in NEN, and indicate that disruption of the IGF2BP1-Myc-EZH2 axis represents a promising approach for targeted therapy of neuroendocrine neoplasms.