The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer
Copyright policy )The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer
AbstractThe 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 m6A-dependent regulation and suggests enhancement of cell cycle progression by m6A-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.
- Martin Luther University Halle-Wittenberg Germany
- UNSW Sydney Australia
1.1 Normal biological development and functioning, 610, 3101 Biochemistry and Cell Biology, Cell Line, Small Molecule Libraries, 3102 Bioinformatics and Computational Biology, Mice, Rare Diseases, Cancer Genomics, anzsrc-for: 34 Chemical sciences, Cell Line, Tumor, Neoplasms, Genetics, 2.1 Biological and endogenous factors, Animals, Humans, anzsrc-for: 31 Biological Sciences, Molecular Biology, 3' Untranslated Regions, Cancer, Neoplastic, Tumor, Human Genome, anzsrc-for: 3101 Biochemistry and Cell Biology, anzsrc-for: 05 Environmental Sciences, RNA-Binding Proteins, E2F Transcription Factors, anzsrc-for: 41 Environmental sciences, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, anzsrc-for: 06 Biological Sciences, Generic health relevance, anzsrc-for: 3102 Bioinformatics and Computational Biology, anzsrc-for: 08 Information and Computing Sciences, E2F1 Transcription Factor, 31 Biological Sciences, Biotechnology
1.1 Normal biological development and functioning, 610, 3101 Biochemistry and Cell Biology, Cell Line, Small Molecule Libraries, 3102 Bioinformatics and Computational Biology, Mice, Rare Diseases, Cancer Genomics, anzsrc-for: 34 Chemical sciences, Cell Line, Tumor, Neoplasms, Genetics, 2.1 Biological and endogenous factors, Animals, Humans, anzsrc-for: 31 Biological Sciences, Molecular Biology, 3' Untranslated Regions, Cancer, Neoplastic, Tumor, Human Genome, anzsrc-for: 3101 Biochemistry and Cell Biology, anzsrc-for: 05 Environmental Sciences, RNA-Binding Proteins, E2F Transcription Factors, anzsrc-for: 41 Environmental sciences, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, anzsrc-for: 06 Biological Sciences, Generic health relevance, anzsrc-for: 3102 Bioinformatics and Computational Biology, anzsrc-for: 08 Information and Computing Sciences, E2F1 Transcription Factor, 31 Biological Sciences, Biotechnology
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