The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer
The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer
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DOI：
10.1093/nar/gkaa653
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发表时间：
2020-09-04
影响因子：
14.9
通讯作者：
Huettelmaier, Stefan
中科院分区：
文献类型：
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作者：
Muller, Simon;Bley, Nadine;Huettelmaier, Stefan
IGF 2 mRNA结合蛋白1（IGF 2BP 1）是一种非催化性转录后肿瘤生长增强子，上调并与实体癌的不良预后相关。然而，保守的效应途径和靶向IGF 2BP 1在癌症中的可行性仍然难以捉摸。我们揭示了IGF 2BP 1是实体癌中E2 F驱动标志的转录后增强子。IGF 2BP 1通过稳定编码该检查点（如E2 F1）的正调节因子的mRNA来促进G1/S细胞周期转换。这种IGF 2BP 1驱动的G1期细胞周期缩短依赖于3 'UTR-、miRNA-和m（6）A-依赖性调节，并表明在癌症中通过m（6）A-修饰增强细胞周期进程。除了E2 F转录因子外，IGF 2BP 1还稳定E2 F驱动的转录物，直接表明该蛋白在癌症中E2 F驱动的基因表达中的转录后“超级”增强子作用。小分子BTYNB通过损害IGF 2BP 1-RNA结合来破坏这种增强子功能。因此，BTYNB干扰实验小鼠肿瘤模型中E2 F驱动的基因表达和肿瘤生长。
The IGF2 mRNA-binding protein 1 (IGF2BP1) is a non-catalytic post-transcriptional enhancer of tumor growth upregulated and associated with adverse prognosis in solid cancers. However, conserved effector pathway(s) and the feasibility of targeting IGF2BP1 in cancer remained elusive. We reveal that IGF2BP1 is a post-transcriptional enhancer of the E2F-driven hallmark in solid cancers. IGF2BP1 promotes G1/S cell cycle transition by stabilizing mRNAs encoding positive regulators of this checkpoint like E2F1. This IGF2BP1-driven shortening of the G1 cell cycle phase relies on 3'UTR-, miRNA- and m(6)A-dependent regulation and suggests enhancement of cell cycle progression by m(6)A-modifications across cancers. In addition to E2F transcription factors, IGF2BP1 also stabilizes E2F-driven transcripts directly indicating post-transcriptional 'super'-enhancer role of the protein in E2F-driven gene expression in cancer. The small molecule BTYNB disrupts this enhancer function by impairing IGF2BP1-RNA association. Consistently, BTYNB interferes with E2F-driven gene expression and tumor growth in experimental mouse tumor models.