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Translational Machinery to Understand and Fight Cancer

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Published Papers

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 53238

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Special Issue Editors

Dr. Virginie Marcel

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Guest Editor

Centre de Recherche en Cancérologie de Lyon, UMR Inserm 1052 - CNRS 5286 - UCBL-CLB, 28, rue Laennec, 69008 Lyon, France
Interests: ribosome; specialized ribosome; chemical modification of rRNA; 2’-O-methylation; rRNA epitranscriptome; translation; cancer; therapy; biomarkers

Dr. Frédéric Catez

E-Mail Website
Guest Editor

Dr. Jean-Jacques Diaz

E-Mail Website
Guest Editor

Cancer Research Center of Lyon - UMR Inserm 1052 CNRS 5286 - Centre Léon Bérard, Lyon, France
Interests: translational regulation; ribosome biology; cancer biology; cancer cell plasticity; proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

With 8.2 million deaths and 32.5 million people living with cancer in 2015, cancer persists in being a major public health issue (WHO, 2018). Understanding the biology of cancer diseases is, more than ever, a challenging goal for the scientific community, and major efforts are necessary to identify original and innovative targets to improve management and life quality of cancer patients. Recent advances in the field of translational control brought to light a new source of molecular mechanisms that directly contribute to cancer and unravelled an unexpected reservoir of novel targets: the translational machinery itself. Indeed, the last 10 years revealed that alteration of the translational machinery components directly contributes in altering gene expression and drives tumorigenesis. Importantly, cancer cells become addicted to these alterations and represent a novel weakness to exploit. In addition to translational factors, ribosomes and tRNAs have also shown novel facets in regulating gene expression that already started to open novel perspectives in cancer management.

This Special Issue of Cells, “Translational Machinery to Understand and Fight Cancer”, is devoted to compile studies revealing the emerging role of each component of the translational machinery in cancer biology, cancer management and as therapeutic target. This Special Issue will draw the current overview of translation in cancer, from the role of translation control and translational machinery in tumorigenesis and cancer progression to the usage of the translational machinery and ribosome biogenesis factors in clinics. We seek submission of reviews addressing the role of translation deregulation in cancer, with a particular focus on dysregulation of translation induced by the translational machinery (specialized ribosome, tRNA modifications, snoRNAs, translation factors). Oncology topics include contribution to tumorigenesis and cancer progression, cancer cell plasticity, cancer stem cells, biomarkers, and therapeutic target validation. We encourage manuscripts that illustrate the contribution of the translational machinery, with a particular interest on ribosome, tRNA and translational factors, in cancer-related topics.

Dr. Virginie Marcel
Dr. Frédéric Catez
Dr. Jean-Jacques Diaz
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ribosome
ribosome biogenesis
ribosome composition
ribosome plasticity
ribosome-modulated translation
specialized ribosome
translational regulation
RNA epigenetics
rRNA chemical modifications
non-coding RNAs
small nucleolar RNAs (snoRNAs)
transfer RNAs (tRNAs)
cancer
ribosome & ribosome biogenesis targeting
translational factor targeting

Published Papers (9 papers)

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Research

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18 pages, 3181 KiB

Open AccessArticle

Uncovering the Translational Regulatory Activity of the Tumor Suppressor BRCA1

by Elise Berthel, Anne Vincent, Lauriane Eberst, Adrian Gabriel Torres, Estelle Dacheux, Catherine Rey, Virginie Marcel, Hermes Paraqindes, Joël Lachuer, Frédéric Catez, Lluis Ribas de Pouplana, Isabelle Treilleux, Jean-Jacques Diaz and Nicole Dalla Venezia

Cells 2020, 9(4), 941; https://doi.org/10.3390/cells9040941 - 10 Apr 2020

Cited by 5 | Viewed by 2689

Abstract

BRCA1 inactivation is a hallmark of familial breast cancer, often associated with aggressive triple negative breast cancers. BRCA1 is a tumor suppressor with known functions in DNA repair, transcription regulation, cell cycle control, and apoptosis. In the present study, we demonstrate that BRCA1 is also a translational regulator. We previously showed that BRCA1 was implicated in translation regulation. Here, we asked whether translational control could be a novel function of BRCA1 that contributes to its tumor suppressive activity. A combination of RNA-binding protein immunoprecipitation, microarray analysis, and polysome profiling, was used to identify the mRNAs that were specifically deregulated under BRCA1 deficiency. Western blot analysis allowed us to confirm at the protein level the deregulated translation of a subset of mRNAs. A unique and dedicated cohort of patients with documented germ-line BRCA1 pathogenic variant statues was set up, and tissue microarrays with the biopsies of these patients were constructed and analyzed by immunohistochemistry for their content in each candidate protein. Here, we show that BRCA1 translationally regulates a subset of mRNAs with which it associates. These mRNAs code for proteins involved in major programs in cancer. Accordingly, the level of these key proteins is correlated with BRCA1 status in breast cancer cell lines and in patient breast tumors. ADAT2, one of these key proteins, is proposed as a predictive biomarker of efficacy of treatments recently recommended to patients with BRCA1 deficiency. This study proposes that translational control may represent a novel molecular mechanism with potential clinical impact through which BRCA1 is a tumor suppressor. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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16 pages, 2926 KiB

Open AccessArticle

Separated Siamese Twins: Intronic Small Nucleolar RNAs and Matched Host Genes May be Altered in Conjunction or Separately in Multiple Cancer Types

by Marianna Penzo, Rosanna Clima, Davide Trerè and Lorenzo Montanaro

Cells 2020, 9(2), 387; https://doi.org/10.3390/cells9020387 - 07 Feb 2020

Cited by 8 | Viewed by 2504

Abstract

Small nucleolar RNAs (snoRNAs) are non-coding RNAs involved in RNA modification and processing. Approximately half of the so far identified snoRNA genes map within the intronic regions of host genes, and their expression, as well as the expression of their host genes, is dependent on transcript splicing and maturation. Growing evidence indicates that mutations and/or deregulations that affect snoRNAs, as well as host genes, play a significant role in oncogenesis. Among the possible factors underlying snoRNA/host gene expression deregulation is copy number alteration (CNA). We analyzed the data available in The Cancer Genome Atlas database, relative to CNA and expression of 295 snoRNA/host gene couples in 10 cancer types, to understand whether the genetic or expression alteration of snoRNAs and their matched host genes would have overlapping trends. Our results show that, counterintuitively, copy number and expression alterations of snoRNAs and matched host genes are not necessarily coupled. In addition, some snoRNA/host genes are mutated and overexpressed recurrently in multiple cancer types. Our findings suggest that the differential contribution to cancer development of both snoRNAs and host genes should always be considered, and that snoRNAs and their host genes may contribute to cancer development in conjunction or independently. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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17 pages, 3998 KiB

Open AccessArticle

Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits

by Elisa Pesce, Annarita Miluzio, Lorenzo Turcano, Claudia Minici, Delia Cirino, Piera Calamita, Nicola Manfrini, Stefania Oliveto, Sara Ricciardi, Renata Grifantini, Massimo Degano, Alberto Bresciani and Stefano Biffo

Cells 2020, 9(1), 172; https://doi.org/10.3390/cells9010172 - 10 Jan 2020

Cited by 13 | Viewed by 4117

Abstract

Eukaryotic initiation factor 6 (eIF6) is necessary for the nucleolar biogenesis of 60S ribosomes. However, most of eIF6 resides in the cytoplasm, where it acts as an initiation factor. eIF6 is necessary for maximal protein synthesis downstream of growth factor stimulation. eIF6 is an antiassociation factor that binds 60S subunits, in turn preventing premature 40S joining and thus the formation of inactive 80S subunits. It is widely thought that eIF6 antiassociation activity is critical for its function. Here, we exploited and improved our assay for eIF6 binding to ribosomes (iRIA) in order to screen for modulators of eIF6 binding to the 60S. Three compounds, eIFsixty-1 (clofazimine), eIFsixty-4, and eIFsixty-6 were identified and characterized. All three inhibit the binding of eIF6 to the 60S in the micromolar range. eIFsixty-4 robustly inhibits cell growth, whereas eIFsixty-1 and eIFsixty-6 might have dose- and cell-specific effects. Puromycin labeling shows that eIF6ixty-4 is a strong global translational inhibitor, whereas the other two are mild modulators. Polysome profiling and RT-qPCR show that all three inhibitors reduce the specific translation of well-known eIF6 targets. In contrast, none of them affect the nucleolar localization of eIF6. These data provide proof of principle that the generation of eIF6 translational modulators is feasible. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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Review

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22 pages, 2392 KiB

Open AccessReview

Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies

by Arnaud Gilles, Léo Frechin, Kundhavai Natchiar, Giulia Biondani, Ottilie von Loeffelholz, Samuel Holvec, Julie-Lisa Malaval, Jean-Yves Winum, Bruno P. Klaholz and Jean-François Peyron

Cells 2020, 9(3), 629; https://doi.org/10.3390/cells9030629 - 05 Mar 2020

Cited by 39 | Viewed by 7308

Abstract

The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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Graphical abstract

23 pages, 1174 KiB

Open AccessReview

snoRNAs Offer Novel Insight and Promising Perspectives for Lung Cancer Understanding and Management

by Nour-El-Houda Mourksi, Chloé Morin, Tanguy Fenouil, Jean-Jacques Diaz and Virginie Marcel

Cells 2020, 9(3), 541; https://doi.org/10.3390/cells9030541 - 26 Feb 2020

Cited by 41 | Viewed by 3936

Abstract

Small nucleolar RNAs (snoRNAs) are non-coding RNAs localized in the nucleolus, where they participate in the cleavage and chemical modification of ribosomal RNAs. Their biogenesis and molecular functions have been extensively studied since their identification in the 1960s. However, their role in cancer has only recently started to emerge. In lung cancer, efforts to profile snoRNA expression have enabled the definition of snoRNA-related signatures, not only in tissues but also in biological fluids, exposing these small RNAs as potential non-invasive biomarkers. Moreover, snoRNAs appear to be essential actors of lung cancer onset and dissemination. They affect diverse cellular functions, from regulation of the cell proliferation/death balance to promotion of cancer cell plasticity. snoRNAs display both oncogenic and tumor suppressive activities that are pivotal in lung cancer tumorigenesis and progression. Altogether, we review how further insight into snoRNAs may improve our understanding of basic lung cancer biology and the development of innovative diagnostic tools and therapies. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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28 pages, 1449 KiB

Open AccessReview

Translational Regulations in Response to Endoplasmic Reticulum Stress in Cancers

by Manon Jaud, Céline Philippe, Doriana Di Bella, Weiwei Tang, Stéphane Pyronnet, Henrik Laurell, Laurent Mazzolini, Kevin Rouault-Pierre and Christian Touriol

Cells 2020, 9(3), 540; https://doi.org/10.3390/cells9030540 - 26 Feb 2020

Cited by 34 | Viewed by 5715

Abstract

During carcinogenesis, almost all the biological processes are modified in one way or another. Among these biological processes affected, anomalies in protein synthesis are common in cancers. Indeed, cancer cells are subjected to a wide range of stresses, which include physical injuries, hypoxia, nutrient starvation, as well as mitotic, oxidative or genotoxic stresses. All of these stresses will cause the accumulation of unfolded proteins in the Endoplasmic Reticulum (ER), which is a major organelle that is involved in protein synthesis, preservation of cellular homeostasis, and adaptation to unfavourable environment. The accumulation of unfolded proteins in the endoplasmic reticulum causes stress triggering an unfolded protein response in order to promote cell survival or to induce apoptosis in case of chronic stress. Transcription and also translational reprogramming are tightly controlled during the unfolded protein response to ensure selective gene expression. The majority of stresses, including ER stress, induce firstly a decrease in global protein synthesis accompanied by the induction of alternative mechanisms for initiating the translation of mRNA, later followed by a translational recovery. After a presentation of ER stress and the UPR response, we will briefly present the different modes of translation initiation, then address the specific translational regulatory mechanisms acting during reticulum stress in cancers and highlight the importance of translational control by ER stress in tumours. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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31 pages, 3670 KiB

Open AccessFeature PaperReview

Ribosome and Translational Control in Stem Cells

by Mathieu Gabut, Fleur Bourdelais and Sébastien Durand

Cells 2020, 9(2), 497; https://doi.org/10.3390/cells9020497 - 21 Feb 2020

Cited by 49 | Viewed by 6982

Abstract

Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in the context of a rapidly developing embryo or in steady-state tissues, respectively. This ability is controlled by complex genetic programs, which are dynamically orchestrated at different steps of gene expression, including chromatin remodeling, mRNA transcription, processing, and stability. In addition to maintaining stem cell homeostasis, these molecular processes need to be rapidly rewired to coordinate complex physiological modifications required to redirect cell fate in response to environmental clues, such as differentiation signals or tissue injuries. Although chromatin remodeling and mRNA expression have been extensively studied in stem cells, accumulating evidence suggests that stem cell transcriptomes and proteomes are poorly correlated and that stem cell properties require finely tuned protein synthesis. In addition, many studies have shown that the biogenesis of the translation machinery, the ribosome, is decisive for sustaining ESC and ASC properties. Therefore, these observations emphasize the importance of translational control in stem cell homeostasis and fate decisions. In this review, we will provide the most recent literature describing how ribosome biogenesis and translational control regulate stem cell functions and are crucial for accommodating proteome remodeling in response to changes in stem cell fate. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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23 pages, 3641 KiB

Open AccessReview

Targeting the RNA Polymerase I Transcription for Cancer Therapy Comes of Age

by Rita Ferreira, John S. Schneekloth, Jr., Konstantin I. Panov, Katherine M. Hannan and Ross D. Hannan

Cells 2020, 9(2), 266; https://doi.org/10.3390/cells9020266 - 21 Jan 2020

Cited by 102 | Viewed by 13199

Abstract

Transcription of the ribosomal RNA genes (rDNA) that encode the three largest ribosomal RNAs (rRNA), is mediated by RNA Polymerase I (Pol I) and is a key regulatory step for ribosomal biogenesis. Although it has been reported over a century ago that the number and size of nucleoli, the site of ribosome biogenesis, are increased in cancer cells, the significance of this observation for cancer etiology was not understood. The realization that the increase in rRNA expression has an active role in cancer progression, not only through increased protein synthesis and thus proliferative capacity but also through control of cellular check points and chromatin structure, has opened up new therapeutic avenues for the treatment of cancer through direct targeting of Pol I transcription. In this review, we discuss the rational of targeting Pol I transcription for the treatment of cancer; review the current cancer therapeutics that target Pol I transcription and discuss the development of novel Pol I-specific inhibitors, their therapeutic potential, challenges and future prospects. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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17 pages, 1770 KiB

Open AccessReview

Cancer Biogenesis in Ribosomopathies

by Sergey O. Sulima, Kim R. Kampen and Kim De Keersmaecker

Cells 2019, 8(3), 229; https://doi.org/10.3390/cells8030229 - 11 Mar 2019

Cited by 54 | Viewed by 5980

Abstract

Ribosomopathies are congenital diseases with defects in ribosome assembly and are characterized by elevated cancer risks. Additionally, somatic mutations in ribosomal proteins have recently been linked to a variety of cancers. Despite a clear correlation between ribosome defects and cancer, the molecular mechanisms by which these defects promote tumorigenesis are unclear. In this review, we focus on the emerging mechanisms that link ribosomal defects in ribosomopathies to cancer progression. This includes functional “onco-specialization” of mutant ribosomes, extra-ribosomal consequences of mutations in ribosomal proteins and ribosome assembly factors, and effects of ribosomal mutations on cellular stress and metabolism. We integrate some of these recent findings in a single model that can partially explain the paradoxical transition from hypo- to hyperproliferation phenotypes, as observed in ribosomopathies. Finally, we discuss the current and potential strategies, and the associated challenges for therapeutic intervention in ribosome-mutant diseases. Full article

(This article belongs to the Special Issue Translational Machinery to Understand and Fight Cancer)

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