The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let-7 family.
Bianca Busch,Nadine Bley,Simon Müller,Markus Glaß,Danny Misiak,Marcell Lederer,Martina Vetter,Hans-Georg Strauß,Christoph Thomssen,Stefan Hüttelmaier +9 more
TLDR
The targeting of the HMGA2-LIN28B-IGF2BP1 triangle is suggested as a promising strategy in cancer treatment because the expression of the triangle factors is inversely correlated with let-7 levels and promoted by LIN28B impairingLet-7 biogenesis.Abstract:
The tumor-suppressive let-7 microRNA family targets various oncogene-encoding mRNAs. We identify the let-7 targets HMGA2, LIN28B and IGF2BP1 to form a let-7 antagonizing self-promoting oncogenic triangle. Surprisingly, 3'-end processing of IGF2BP1 mRNAs is unaltered in aggressive cancers and tumor-derived cells although IGF2BP1 synthesis was proposed to escape let-7 attack by APA-dependent (alternative polyadenylation) 3' UTR shortening. However, the expression of the triangle factors is inversely correlated with let-7 levels and promoted by LIN28B impairing let-7 biogenesis. Moreover, IGF2BP1 enhances the expression of all triangle factors by recruiting the respective mRNAs in mRNPs lacking AGO proteins and let-7 miRNAs. This indicates that the downregulation of let-7, largely facilitated by LIN28B upregulation, and the protection of let-7 target mRNAs by IGF2BP1-directed shielding in mRNPs synergize in enhancing the expression of triangle factors. The oncogenic potential of this triangle was confirmed in ovarian cancer (OC)-derived ES-2 cells transduced with let-7 targeting decoys. In these, the depletion of HMGA2 only diminishes tumor cell growth under permissive conditions. The depletion of LIN28B and more prominently IGF2BP1 severely impairs tumor cell viability, self-renewal and 2D as well as 3D migration. In conclusion, this suggests the targeting of the HMGA2-LIN28B-IGF2BP1 triangle as a promising strategy in cancer treatment.read more
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Functions of N6-methyladenosine and its role in cancer.
TL;DR: Al Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR and corresponding potential targets in cancer therapy are reviewed.
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IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner
Simon Müller,Markus Glaß,Anurag Kumar Singh,Jacob Haase,Nadine Bley,Tommy Fuchs,Marcell Lederer,Andreas Dahl,Huilin Huang,Huilin Huang,Jianjun Chen,Jianjun Chen,Guido Posern,Stefan Hüttelmaier +13 more
TL;DR: Findings identify the SRF/IGF2BP1, miRNome- and m6A-dependent control of gene expression as a conserved oncogenic driver network in cancer.
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