The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer

Müller, Simon; Bley, Nadine; Busch, Bianca; Glaß, Markus; Lederer, Marcell; Misiak, Claudia; Fuchs, Tommy; Wedler, Alice; Haase, Jacob; Bertoldo, Jean B.; Michl, Patrick; Hüttelmaier, Stefan

doi:10.1093/nar/gkaa653

Cited by 116 publications

(156 citation statements)

References 43 publications

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“…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). However, only for the regulation of E2F-driven gene expression, a strongly conserved role of IGF2BP1 in promoting gene expression of E2F1-3 transcription factors and some of the target transcripts, e.g., MKI67, was reported (Müller et al, 2020).…”

Section: Introductionsupporting

confidence: 64%

“…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). However, only for the regulation of E2F-driven gene expression, a strongly conserved role of IGF2BP1 in promoting gene expression of E2F1-3 transcription factors and some of the target transcripts, e.g., MKI67, was reported (Müller et al, 2020). In support of these findings, studies in distinct cancer models confirm a role of IGF2BP1 in promoting additional cancer hallmark pathways, including MYC/MYCN-driven gene expression demonstrated in ovarian cancer (Köbel et al, 2007), liver cancer (Gutschner et al, 2014; and neuroblastoma (Bell et al, 2015), as well as KRAS-driven signaling in lung adenocarcinoma (Rosenfeld et al, 2019).…”

Section: Introductionsupporting

confidence: 55%

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IGF2BP1, a Conserved Regulator of RNA Turnover in Cancer

Glaß

Misiak

Bley

et al. 2021

Front. Mol. Biosci.

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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.

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Section: Introductionsupporting

confidence: 64%

Section: Introductionsupporting

confidence: 55%

IGF2BP1, a Conserved Regulator of RNA Turnover in Cancer

Glaß

Misiak

Bley

et al. 2021

Front. Mol. Biosci.

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“…The host genes for the FLEXI RNAs in cluster V are enriched in only a few GO terms for each RBP. Four of these proteins function in splicing regulation (LSM11, PCBP2, RBFOX1, and GPKOW) and three others are notable regulatory proteins: IGF2BP1 (insulin-like growth factor 2 mRNA-binding protein1), which functions in cell cycle regulation (Müller et al 2020); G3BP1 (Ras GTPase-activating protein binding protein 1), a helicase that plays an essential role in innate immunity, functions in stress granule assembly, is associated with cellular senescence, and regulates important signaling pathways (Zhang et al 2019; Eiermann et al 2020; Omer et al 2020); and PABPN1 (polyadenylate-binding protein 2), a crucial player in double-strand-break repair (Gavish-Izakson et al 2018). Three of these proteins (IGF2BP1, LSM11, and G3BP1) were among those binding to substantial subsets of FLEXIs that lacked annotated binding sites for the five core spliceosomal proteins (see above).…”

Section: Resultsmentioning

confidence: 99%

Human cells contain myriad excised linear intron RNAs with links to gene regulation and potential utility as biomarkers

Yao

Winans

et al. 2020

Preprint

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We used thermostable group II intron reverse transcriptase sequencing (TGIRT-seq), which gives end-to-end sequence reads of highly structured RNAs, to identify >8,000 short (≤300 nt) full-length excised intron (FLEXI) RNAs in human cells. Most FLEXI RNAs are predicted to have stable secondary structures, making them difficult to detect by other RNA-seq methods. Some FLEXI RNAs correspond to annotated mirtron pre-miRNAs (introns that are processed into functional miRNAs) or agotrons (introns that bind AGO2 and function in a miRNA-like manner), but the vast majority had not been identified or characterized previously. FLEXI RNA profiles are cell-type specific, reflecting differences in host gene transcription, alternative splicing, or intron RNA turnover, and comparisons of matched tumor and healthy tissues from breast cancer patients and cell lines revealed hundreds of differences in FLEXI RNA expression. About half of the FLEXI RNAs contained one or more experimentally identified binding sites for a spliceosomal protein, AGO1-4, DICER, or a number of different regulatory proteins, suggesting multiple ways in which FLEXIs could contribute to the regulation of gene expression. As FLEXI RNAs are linked to the expression of thousands of protein-coding and lncRNA genes, they potentially constitute a new class of broadly applicable, highly discriminatory biomarkers for human diseases.

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“…1G) and functional studies suggest a putative connection to the secretory cell signatures 'Cell Cycle' and 'EMT' [14]. Moreover, IGF2BP1 was recently shown to modulate the cell cycle in an E2F1-dependent manner [32]. In EOC-derived cells, IGF2BP1 promotes invasive growth by stimulating SRC/ERK-signalling.…”

Section: Discussionmentioning

confidence: 99%

“…In cancer, IGF2BP1's main function is the partially m 6 A-dependent (N [6]-methyladenosine) impairment of miRNA-directed mRNA decay by binding to target transcripts via its four KH (hnRNPK homology) domains [21,[24][25][26][27][28][29][30][31]. This results in elevated expression of oncogenic factors like LIN28B, HMGA2, MYC, SRF, E2F1 and ERK2 [21,24,25,32,33]. During development, the spatially restricted synthesis of ACTB is essentially controlled by the SRC-directed phosphorylation of IGF2BP1 [34].…”

Section: Introductionmentioning

confidence: 99%

IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

et al. 2020

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Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HGSOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here, we show that the IGF2 mRNA-binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HGSOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in an RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signalling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation, only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rationale for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymallike HGSOC.

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The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer

Cited by 116 publications

References 43 publications

IGF2BP1, a Conserved Regulator of RNA Turnover in Cancer

IGF2BP1, a Conserved Regulator of RNA Turnover in Cancer

Human cells contain myriad excised linear intron RNAs with links to gene regulation and potential utility as biomarkers

IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

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