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      RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives

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          Abstract

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          RNA-binding proteins (RBPs) play central roles in regulating posttranscriptional expression of genes. Many of them are known to be deregulated in a wide variety of cancers. Dysregulated RBPs influence the expression levels of target RNAs related to cancer phenotypes, such as proliferation, apoptosis, angiogenesis, senescence, and EMT/invasion/metastasis. Thus, understanding the molecular functions of RBPs and their roles in cancer-related phenotypes can lead to improved therapeutic strategies.

          Abstract

          RNA-binding proteins (RBPs) crucially regulate gene expression through post-transcriptional regulation, such as by modulating microRNA (miRNA) processing and the alternative splicing, alternative polyadenylation, subcellular localization, stability, and translation of RNAs. More than 1500 RBPs have been identified to date, and many of them are known to be deregulated in cancer. Alterations in the expression and localization of RBPs can influence the expression levels of oncogenes, tumor-suppressor genes, and genome stability-related genes. RBP-mediated gene regulation can lead to diverse cancer-related cellular phenotypes, such as proliferation, apoptosis, angiogenesis, senescence, and epithelial-mesenchymal transition (EMT)/invasion/metastasis. This regulation can also be associated with cancer prognosis. Thus, RBPs can be potential targets for the development of therapeutics for the cancer treatment. In this review, we describe the molecular functions of RBPs, their roles in cancer-related cellular phenotypes, and various approaches that may be used to target RBPs for cancer treatment.

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          Recognition of RNA N 6 -methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

          Huilin Huang, Hengyou Weng, Wenju Sun … (2018)
          N 6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTHDF2, IGF2BPs promote the stability and storage of their target mRNAs (e.g., MYC) in an m6A-depedent manner under normal and stress conditions and thus affect gene expression output. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Our work therefore reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.
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            The RNA binding protein quaking regulates formation of circRNAs.

            Simon Conn, Katherine A. Pillman, John Toubia … (2015)
            Circular RNAs (circRNAs), formed by non-sequential back-splicing of pre-mRNA transcripts, are a widespread form of non-coding RNA in animal cells. However, it is unclear whether the majority of circRNAs represent splicing by-products without function or are produced in a regulated manner to carry out specific cellular functions. We show that hundreds of circRNAs are regulated during human epithelial-mesenchymal transition (EMT) and find that the production of over one-third of abundant circRNAs is dynamically regulated by the alternative splicing factor, Quaking (QKI), which itself is regulated during EMT. Furthermore, by modulating QKI levels, we show the effect on circRNA abundance is dependent on intronic QKI binding motifs. Critically, the addition of QKI motifs is sufficient to induce de novo circRNA formation from transcripts that are normally linearly spliced. These findings demonstrate circRNAs are both purposefully synthesized and regulated by cell-type specific mechanisms, suggesting they play specific biological roles in EMT.
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              A census of human RNA-binding proteins.

              Stefanie Gerstberger, Markus Hafner, Thomas Tuschl (2014)
              Post-transcriptional gene regulation (PTGR) concerns processes involved in the maturation, transport, stability and translation of coding and non-coding RNAs. RNA-binding proteins (RBPs) and ribonucleoproteins coordinate RNA processing and PTGR. The introduction of large-scale quantitative methods, such as next-generation sequencing and modern protein mass spectrometry, has renewed interest in the investigation of PTGR and the protein factors involved at a systems-biology level. Here, we present a census of 1,542 manually curated RBPs that we have analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression. Our analysis is a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 21 September 2020
                Publication date Collection: September 2020
                Volume: 12
                Issue: 9
                Electronic Location Identifier: 2699
                Affiliations
                [1 ]Medical Research Center, College of Medicine, Inha University, Incheon 22212, Korea; dongheekang@ 123456inha.edu (D.K.); 318067@ 123456inha.ac.kr (Y.L.)
                [2 ]Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Korea
                [3 ]Program in Biomedical Science & Engineering, Inha University Graduate School, Incheon 22212, Korea
                Author notes
                [* ]Correspondence: jaeslee@ 123456inha.ac.kr ; Tel.: +82-32-860-9832
                [†]

                These authors contributed equally to this work.

                Article
                Publisher ID: cancers-12-02699
                DOI: 10.3390/cancers12092699
                PMC ID: 7563379
                PubMed ID: 32967226
                SO-VID: fe658c00-ebcd-46a0-bb0c-948ca95db043
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 23 July 2020
                Date accepted : 18 September 2020
                Categories
                Subject: Review

                Keywords: rna-binding proteins (rbps),mechanistic function,cancer phenotype,cancer therapy
                Data availability:
                Keywords: rna-binding proteins (rbps), mechanistic function, cancer phenotype, cancer therapy

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