IGF2BP1, a Conserved Regulator of RNA Turnover in Cancer.

Markus Glaß,Alexander Rausch,Stefan Hüttelmaier,Nadine Bley,Danny Misiak,Simon Müller,Bianca Busch,Sven Hagemann

doi:10.3389/fmolb.2021.632219

Markus Glaß, Alexander Rausch + Show 6 more

Open Access

https://doi.org/10.3389/fmolb.2021.632219

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Abstract

The oncofetal IGF2 mRNA-binding protein 1 (IGF2BP1) promotes tumor progression in a variety of solid tumors and its expression is associated with adverse prognosis. The main role proposed for IGF2BP1 in cancer cells is the stabilization of mRNAs encoding pro-oncogenic factors. Several IGF2BP1-RNA association studies, however, revealed a plethora of putative IGF2BP1-RNA targets. Thus, at present the main conserved target RNAs and pathways controlled by IGF2BP1 in cancer remain elusive. In this study, we present a set of genes and cancer hallmark pathways showing a conserved pattern of deregulation in dependence of IGF2BP1 expression in cancer cell lines. By the integrative analysis of these findings with publicly available cancer transcriptome and IGF2BP1-RNA association data, we compiled a set of prime candidate target mRNAs. These analyses confirm a pivotal role of IGF2BP1 in controlling cancer cell cycle progression and reveal novel cancer hallmark pathways influenced by IGF2BP1. For three novel target mRNAs identified by these studies, namely AURKA, HDLBP and YWHAZ, we confirm IGF2BP1 mRNA stabilization. In sum our findings confirm and expand previous findings on the pivotal role of IGF2BP1 in promoting oncogenic gene expression by stabilizing target mRNAs in a mainly 3’UTR, m6A-, miRNA-, and potentially AU-rich element dependent manner.

Highlights

The oncofetal IGF2 mRNA-binding protein 1 (IGF2BP1) is a crucial regulator of tumor and stem cell fate and its elevated expression in a multitude of tumors is associated with poor prognosis (Degrauwe et al, 2016; Hattori et al, 2016)
In the here presented study we present an analysis pipeline for the identification of conserved cancer hallmark pathways influenced by IGF2BP1 by stabilizing target mRNAs encoding prooncogenic factors
Gene set enrichment analyses (GSEA) of candidate target mRNA of IGF2BP1 support a pivotal role of the protein in cancer cell cycle progression, but highlight cancer hallmark pathways influenced by IGF2BP1

Summary

Introduction

The oncofetal IGF2 mRNA-binding protein 1 (IGF2BP1) is a crucial regulator of tumor and stem cell fate and its elevated expression in a multitude of tumors is associated with poor prognosis (Degrauwe et al, 2016; Hattori et al, 2016). This was originally described for the IGF2BP1-dependent enhancement of BTRC (β-TrCP1) expression (Noubissi et al, 2006; Elcheva et al, 2009) In support of these findings the impairment of miRNA-dependent regulation was demonstrated in a variety of cancer cell models for various mRNAs including pro-oncogenic factors like LIN28B and HMGA2 (Busch et al, 2016), MITF (Goswami et al, 2015), MKI67 (Gutschner et al, 2014; Müller et al, 2020) and SRF (Müller et al, 2019). RNA-binding information of IGF2BP1 derived by CLIP studies as well as predicted miRNA-targeting, 3’UTR properties and m6A-modification of candidate target mRNAs were considered These studies confirm previous target mRNAs and IGF2BP1’s role in promoting cancer cell cycle progression. These studies suggest novel, conserved effector pathways and target transcripts of the protein, three of which (AURKA, HDLBP and YWHAZ) were validated as target mRNAs stabilized by IGF2BP1

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