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20 pages, 3105 KiB

Open AccessArticle

Proteome-Wide Identification of RNA-Dependent Proteins in Lung Cancer Cells

by Varshni Rajagopal, Astrid-Solveig Loubal, Niklas Engel, Elsa Wassmer, Jeanette Seiler, Oliver Schilling, Maiwen Caudron-Herger and Sven Diederichs

Cancers 2022, 14(24), 6109; https://doi.org/10.3390/cancers14246109 - 12 Dec 2022

Cited by 3 | Viewed by 2703

Abstract

Following the concept of RNA dependence and exploiting its application in the R-DeeP screening approach, we have identified RNA-dependent proteins in A549 lung adenocarcinoma cells. RNA-dependent proteins are defined as proteins whose interactome depends on RNA and thus entails RNA-binding proteins (RBPs) as [...] Read more.

Following the concept of RNA dependence and exploiting its application in the R-DeeP screening approach, we have identified RNA-dependent proteins in A549 lung adenocarcinoma cells. RNA-dependent proteins are defined as proteins whose interactome depends on RNA and thus entails RNA-binding proteins (RBPs) as well as proteins in ribonucleoprotein complexes (RNPs) without direct RNA interaction. With this proteome-wide technique based on sucrose density gradient ultracentrifugation and fractionation followed by quantitative mass spectrometry and bioinformatic analysis, we have identified 1189 RNA-dependent proteins including 170 proteins which had never been linked to RNA before. R-DeeP provides quantitative information on the fraction of a protein being RNA-dependent as well as it allows the reconstruction of protein complexes based on co-segregation. The RNA dependence of three newly identified RNA-dependent proteins, DOCK5, ELMO2, also known as CED12A, and ABRAXAS1, also known as CCDC98, was validated using western blot analysis, and the direct RNA interaction was verified by iCLIP2 for the migration-related protein DOCK5 and the mitosis-related protein ABRAXAS1. The R-DeeP 2.0 database provides proteome-wide and cell line-specific information from A549 and HeLa S3 cells on proteins and their RNA dependence to contribute to understanding the functional role of RNA and RNA-binding proteins in cancer cells. Full article

(This article belongs to the Special Issue The Role and Therapeutic Target Potential of RBPs in Cancer)

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17 pages, 2138 KiB

Open AccessArticle

IGF2BP1 Promotes Proliferation of Neuroendocrine Neoplasms by Post-Transcriptional Enhancement of EZH2

by Florian Sperling, Danny Misiak, Stefan Hüttelmaier, Patrick Michl and Heidi Griesmann

Cancers 2022, 14(9), 2121; https://doi.org/10.3390/cancers14092121 - 24 Apr 2022

Cited by 10 | Viewed by 3353

Abstract

Neuroendocrine neoplasms (NENs) represent a heterogenous class of highly vascularized neoplasms that are increasing in prevalence and are predominantly diagnosed at a metastatic state. The molecular mechanisms leading to tumor initiation, metastasis, and chemoresistance are still under investigation. Hence, identification of novel therapeutic [...] Read more.

Neuroendocrine neoplasms (NENs) represent a heterogenous class of highly vascularized neoplasms that are increasing in prevalence and are predominantly diagnosed at a metastatic state. The molecular mechanisms leading to tumor initiation, metastasis, and chemoresistance are still under investigation. Hence, identification of novel therapeutic targets is of great interest. Here, we demonstrate that the RNA-binding Protein IGF2BP1 is a post-transcriptional regulator of components of the Polycomb repressive complex 2 (PRC2), an epigenic modifier affecting transcriptional regulation and proliferation: Comprehensive in silico analyses along with in vitro experiments showed that IGF2BP1 promotes neuroendocrine tumor cell proliferation by stabilizing the mRNA of Enhancer of Zeste 2 (EZH2), the catalytic subunit of PRC2, which represses gene expression by tri-methylation of histone H3 at lysine 27 (H3K27me3). The IGF2BP1-driven stabilization and protection of EZH2 mRNA is m6A-dependent and enhances EZH2 protein levels which stimulates cell cycle progression by silencing cell cycle arrest genes through enhanced H3K27 tri-methylation. Therapeutic inhibition of IGF2BP1 destabilizes EZH2 mRNA and results in a reduced cell proliferation, paralleled by an increase in G1 and sub-G1 phases. Combined targeting of IGF2BP1, EZH2, and Myc, a transcriptional activator of EZH2 and well-known target of IGF2BP1 cooperatively induces tumor cell apoptosis. Our data identify IGF2BP1 as an important driver of tumor progression in NEN, and indicate that disruption of the IGF2BP1-Myc-EZH2 axis represents a promising approach for targeted therapy of neuroendocrine neoplasms. Full article

(This article belongs to the Special Issue The Role and Therapeutic Target Potential of RBPs in Cancer)

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22 pages, 3985 KiB

Open AccessArticle

TIA1 Loss Exacerbates Fatty Liver Disease but Exerts a Dual Role in Hepatocarcinogenesis

by Dobrochna Dolicka, Szabolcs Zahoran, Marta Correia de Sousa, Monika Gjorgjieva, Christine Sempoux, Margot Fournier, Christine Maeder, Martine A. Collart, Michelangelo Foti and Cyril Sobolewski

Cancers 2022, 14(7), 1704; https://doi.org/10.3390/cancers14071704 - 27 Mar 2022

Cited by 1 | Viewed by 3188

Abstract

Alterations in specific RNA-binding protein expression/activity importantly contribute to the development of fatty liver disease (FLD) and hepatocellular carcinoma (HCC). In particular, adenylate–uridylate-rich element binding proteins (AUBPs) were reported to control the post-transcriptional regulation of genes involved in both metabolic and cancerous processes. [...] Read more.

Alterations in specific RNA-binding protein expression/activity importantly contribute to the development of fatty liver disease (FLD) and hepatocellular carcinoma (HCC). In particular, adenylate–uridylate-rich element binding proteins (AUBPs) were reported to control the post-transcriptional regulation of genes involved in both metabolic and cancerous processes. Herein, we investigated the pathophysiological functions of the AUBP, T-cell-restricted intracellular antigen-1 (TIA1) in the development of FLD and HCC. Analysis of TIA1 expression in mouse and human models of FLD and HCC indicated that TIA1 is downregulated in human HCC. In vivo silencing of TIA1 using AAV8-delivered shRNAs in mice worsens hepatic steatosis and fibrosis induced by a methionine and choline-deficient diet and increases the hepatic tumor burden in liver-specific PTEN knockout (LPTENKO) mice. In contrast, our in vitro data indicated that TIA1 expression promoted proliferation and migration in HCC cell lines, thus suggesting a dual and context-dependent role for TIA1 in tumor initiation versus progression. Consistent with a dual function of TIA1 in tumorigenesis, translatome analysis revealed that TIA1 appears to control the expression of both pro- and anti-tumorigenic factors in hepatic cancer cells. This duality of TIA1′s function in hepatocarcinogenesis calls for cautiousness when considering TIA1 as a therapeutic target or biomarker in HCC. Full article

(This article belongs to the Special Issue The Role and Therapeutic Target Potential of RBPs in Cancer)

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Review

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22 pages, 1779 KiB

Open AccessReview

RNA-Binding Proteins in Bladder Cancer

by Yuanhui Gao, Hui Cao, Denggao Huang, Linlin Zheng, Zhenyu Nie and Shufang Zhang

Cancers 2023, 15(4), 1150; https://doi.org/10.3390/cancers15041150 - 10 Feb 2023

Cited by 4 | Viewed by 2386

Abstract

RNA-binding proteins (RBPs) are key regulators of transcription and translation, with highly dynamic spatio-temporal regulation. They are usually involved in the regulation of RNA splicing, polyadenylation, and mRNA stability and mediate processes such as mRNA localization and translation, thereby affecting the RNA life [...] Read more.

RNA-binding proteins (RBPs) are key regulators of transcription and translation, with highly dynamic spatio-temporal regulation. They are usually involved in the regulation of RNA splicing, polyadenylation, and mRNA stability and mediate processes such as mRNA localization and translation, thereby affecting the RNA life cycle and causing the production of abnormal protein phenotypes that lead to tumorigenesis and development. Accumulating evidence supports that RBPs play critical roles in vital life processes, such as bladder cancer initiation, progression, metastasis, and drug resistance. Uncovering the regulatory mechanisms of RBPs in bladder cancer is aimed at addressing the occurrence and progression of bladder cancer and finding new therapies for cancer treatment. This article reviews the effects and mechanisms of several RBPs on bladder cancer and summarizes the different types of RBPs involved in the progression of bladder cancer and the potential molecular mechanisms by which they are regulated, with a view to providing information for basic and clinical researchers. Full article

(This article belongs to the Special Issue The Role and Therapeutic Target Potential of RBPs in Cancer)

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13 pages, 1076 KiB

Open AccessReview

Pathogenic Roles of RNA-Binding Proteins in Sarcomas

by Yu Hai, Asuka Kawachi, Xiaodong He and Akihide Yoshimi

Cancers 2022, 14(15), 3812; https://doi.org/10.3390/cancers14153812 - 5 Aug 2022

Cited by 3 | Viewed by 3003

Abstract

RNA-binding proteins (RBPs) are proteins that physically and functionally bind to RNA to regulate the RNA metabolism such as alternative splicing, polyadenylation, transport, maintenance of stability, localization, and translation. There is accumulating evidence that dysregulated RBPs play an essential role in the pathogenesis [...] Read more.

RNA-binding proteins (RBPs) are proteins that physically and functionally bind to RNA to regulate the RNA metabolism such as alternative splicing, polyadenylation, transport, maintenance of stability, localization, and translation. There is accumulating evidence that dysregulated RBPs play an essential role in the pathogenesis of malignant tumors including a variety of types of sarcomas. On the other hand, prognosis of patients with sarcoma, especially with sarcoma in advanced stages, is very poor, and almost no effective standard treatment has been established for most of types of sarcomas so far, highlighting the urgent need for identifying novel therapeutic targets based on the deep understanding of pathogenesis. Therefore, defining the network of interactions between RBPs and disease-related RNA targets will contribute to a better understanding of sarcomagenesis and identification of a novel therapeutic target for sarcomas. Full article

(This article belongs to the Special Issue The Role and Therapeutic Target Potential of RBPs in Cancer)

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30 pages, 2460 KiB

Open AccessReview

MicroRNAs, Tristetraprolin Family Members and HuR: A Complex Interplay Controlling Cancer-Related Processes

by Cyril Sobolewski, Laurent Dubuquoy and Noémie Legrand

Cancers 2022, 14(14), 3516; https://doi.org/10.3390/cancers14143516 - 20 Jul 2022

Cited by 7 | Viewed by 3074

Abstract

MicroRNAs represent the most characterized post-transcriptional regulators of gene expression. Their altered expression importantly contributes to the development of a wide range of metabolic and inflammatory diseases but also cancers. Accordingly, a myriad of studies has suggested novel therapeutic approaches aiming at inhibiting [...] Read more.

MicroRNAs represent the most characterized post-transcriptional regulators of gene expression. Their altered expression importantly contributes to the development of a wide range of metabolic and inflammatory diseases but also cancers. Accordingly, a myriad of studies has suggested novel therapeutic approaches aiming at inhibiting or restoring the expression of miRNAs in human diseases. However, the influence of other trans-acting factors, such as long-noncoding RNAs or RNA-Binding-Proteins, which compete, interfere, or cooperate with miRNAs-dependent functions, indicate that this regulatory mechanism is much more complex than initially thought, thus questioning the current models considering individuals regulators. In this review, we discuss the interplay existing between miRNAs and the AU-Rich Element Binding Proteins (AUBPs), HuR and tristetraprolin family members (TTP, BRF1 and BRF2), which importantly control the fate of mRNA and whose alterations have also been associated with the development of a wide range of chronic disorders and cancers. Deciphering the interplay between these proteins and miRNAs represents an important challenge to fully characterize the post-transcriptional regulation of pro-tumorigenic processes and design new and efficient therapeutic approaches. Full article

(This article belongs to the Special Issue The Role and Therapeutic Target Potential of RBPs in Cancer)

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14 pages, 1149 KiB

Open AccessReview

RBM24 in the Post-Transcriptional Regulation of Cancer Progression: Anti-Tumor or Pro-Tumor Activity?

by De-Li Shi

Cancers 2022, 14(7), 1843; https://doi.org/10.3390/cancers14071843 - 6 Apr 2022

Cited by 7 | Viewed by 4844

Abstract

RNA-binding proteins are critical post-transcriptional regulators of gene expression. They are implicated in a wide range of physiological and pathological processes by modulating nearly every aspect of RNA metabolisms. Alterations in their expression and function disrupt tissue homeostasis and lead to the occurrence [...] Read more.

RNA-binding proteins are critical post-transcriptional regulators of gene expression. They are implicated in a wide range of physiological and pathological processes by modulating nearly every aspect of RNA metabolisms. Alterations in their expression and function disrupt tissue homeostasis and lead to the occurrence of various cancers. RBM24 is a highly conserved protein that binds to a large spectrum of target mRNAs and regulates many post-transcriptional events ranging from pre-mRNA splicing to mRNA stability, polyadenylation and translation. Studies using different animal models indicate that it plays an essential role in promoting cellular differentiation during organogenesis and tissue regeneration. Evidence is also accumulating that its dysregulation frequently occurs across human cancers. In several tissues, RBM24 clearly functions as a tumor suppressor, which is consistent with its inhibitory potential on cell proliferation. However, upregulation of RBM24 in other cancers appears to promote tumor growth. There is a possibility that RBM24 displays both anti-tumor and pro-tumor activities, which may be regulated in part through differential interactions with its protein partners and by its post-translational modifications. This makes it a potential biomarker for diagnosis and prognosis, as well as a therapeutic target for cancer treatment. The challenge remains to determine the post-transcriptional mechanisms by which RBM24 modulates gene expression and tumor progression in a context- or background-dependent manner. This review discusses recent findings on the potential function of RBM24 in tumorigenesis and provides future directions for better understanding its regulatory role in cancer cells. Full article

(This article belongs to the Special Issue The Role and Therapeutic Target Potential of RBPs in Cancer)

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24 pages, 2013 KiB

Open AccessReview

RBM22, a Key Player of Pre-mRNA Splicing and Gene Expression Regulation, Is Altered in Cancer

by Benoît Soubise, Yan Jiang, Nathalie Douet-Guilbert and Marie-Bérengère Troadec

Cancers 2022, 14(3), 643; https://doi.org/10.3390/cancers14030643 - 27 Jan 2022

Cited by 13 | Viewed by 5227

Abstract

RNA-Binding Proteins (RBP) are very diverse and cover a large number of functions in the cells. This review focuses on RBM22, a gene encoding an RBP and belonging to the RNA-Binding Motif (RBM) family of genes. RBM22 presents a Zinc Finger like and [...] Read more.

RNA-Binding Proteins (RBP) are very diverse and cover a large number of functions in the cells. This review focuses on RBM22, a gene encoding an RBP and belonging to the RNA-Binding Motif (RBM) family of genes. RBM22 presents a Zinc Finger like and a Zinc Finger domain, an RNA-Recognition Motif (RRM), and a Proline-Rich domain with a general structure suggesting a fusion of two yeast genes during evolution: Cwc2 and Ecm2. RBM22 is mainly involved in pre-mRNA splicing, playing the essential role of maintaining the conformation of the catalytic core of the spliceosome and acting as a bridge between the catalytic core and other essential protein components of the spliceosome. RBM22 is also involved in gene regulation, and is able to bind DNA, acting as a bona fide transcription factor on a large number of target genes. Undoubtedly due to its wide scope in the regulation of gene expression, RBM22 has been associated with several pathologies and, notably, with the aggressiveness of cancer cells and with the phenotype of a myelodysplastic syndrome. Mutations, enforced expression level, and haploinsufficiency of RBM22 gene are observed in those diseases. RBM22 could represent a potential therapeutic target in specific diseases, and, notably, in cancer. Full article

(This article belongs to the Special Issue The Role and Therapeutic Target Potential of RBPs in Cancer)

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