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1
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Ramirez C, Perenthaler E, Lauria F, Tebaldi T, Viero G. Computational limitations and future needs to unravel the full potential of 2'-O-Methylation and C/D box snoRNAs. RNA Biol 2025. [PMID: 40377202 DOI: 10.1080/15476286.2025.2506712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 05/05/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025] Open
Abstract
This review evaluates the current state of C/D snoRNA databases and prediction tools in relation to 2'-O-methylation (2'-O-Me). It highlights the limitations of existing resources in accurately annotating and predicting guide snoRNAs, particularly for newly identified 2"-O-Me sites. We emphasize the need for advanced computational approaches specifically tailored to 2"-O-Me to enable the discovery and functional analysis of snoRNAs. Given the growing importance of 2'-O-Me in areas such as cancer epitranscriptomics, ribosome biogenesis, and heterogeneity, existing tools remain inadequate. As 2'-O-Me gains recognition as a potential biomarker and therapeutic target, more sophisticated methods are urgently needed to improve snoRNA annotation and prediction, facilitating biomedical advancements.
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Affiliation(s)
- Christian Ramirez
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | | | | | - Toma Tebaldi
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
- Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA
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2
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Ponti D. The Nucleolus: A Central Hub for Ribosome Biogenesis and Cellular Regulatory Signals. Int J Mol Sci 2025; 26:4174. [PMID: 40362410 PMCID: PMC12071546 DOI: 10.3390/ijms26094174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/18/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The nucleolus is the most prominent nuclear domain in eukaryotic cells, primarily responsible for ribosome biogenesis. It synthesizes and processes precursor ribosomal RNA (pre-rRNA) into mature rRNAs, assembling the 40S and 60S ribosomal subunits, which later form the 80S ribosome-the essential molecular machine for protein synthesis. Beyond ribosome production, the nucleolus lacks a delimiting membrane, allowing it to rapidly regulate cellular homeostasis by sequestering key stress response factors. This adaptability enables dynamic changes in size, number, and protein composition in response to cellular stress and signaling. Recent research highlights the nucleolus as a critical regulator of chemoresistance. Given its central role in cell survival and stress adaptation, the nucleolus has become an attractive therapeutic target, particularly in cancer treatment. A deeper understanding of nucleolar metabolism could pave the way for novel therapeutic strategies against various human diseases.
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Affiliation(s)
- Donatella Ponti
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso Della Repubblica 79, 04100 Latina, Italy
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3
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Brunchault MR, Hesse AM, Schaeffer J, Fröhlich A, Saintpierre A, Decourt C, Combes F, Nawabi H, Couté Y, Belin S. Proteomics-based characterization of ribosome heterogeneity in adult mouse organs. Cell Mol Life Sci 2025; 82:175. [PMID: 40272563 PMCID: PMC12022211 DOI: 10.1007/s00018-025-05708-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 03/25/2025] [Accepted: 04/09/2025] [Indexed: 04/25/2025]
Abstract
The translation process, leading to protein synthesis from mRNA, has been long thought to be invariable in all cellular organisms. Increasing evidence shows that it is finely regulated by variable features of the translation machinery. Notably, ribosomes, the functional units of protein synthesis, are suggested to display variations in their composition, depending on the developmental stage, cell type or physio-pathological context, thus hinting a new level of actionable regulation of gene expression. Yet, a comprehensive map of the heterogeneity of ribosome composition in ribosomal proteins (RPs) in different organs and tissues is not available. In this work, we explored tissue-specific ribosome heterogeneity using mass spectrometry-based quantitative proteomic characterization of ribosomal fractions purified from 14 adult mouse organs and tissues. We performed crossed clustering and statistical analyses of RP composition to highlight stable, variable and tissue-specific RPs across organs and tissues. Focusing on specific RPs, we validated their varying abundances using a targeted proteomic approach and western blot analyses, providing further insights into the tissue-specific ribosome RP signature. Finally, we investigated the origin of RP variations in ribosome fraction of the different tissues, by comparing RP relative amounts in our ribosomal proteomic dataset with their corresponding transcript abundances in three independent transcriptomic datasets. Interestingly, we found that, in some tissues, the RP abundance in purified ribosomes does not always correlate with the corresponding RP transcript level, arguing for a translational regulation of RP expression, and/or a regulated incorporation of RPs into ribosomes. Altogether, our data support the notion of a tissue-specific RP signature of ribosomes, which opens avenues to study how specific ribosomal composition provides an additional level of regulation to control gene expression in different tissues and organs.
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Affiliation(s)
- Marie R Brunchault
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Anne-Marie Hesse
- Univ. Grenoble Alpes, INSERM, CEA, UA13 BGE, CNRS, CEA, FR2048, 38000, Grenoble, France
| | - Julia Schaeffer
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
- IBDM, CNRS, UMR 7288, Aix-Marseille Université, Marseille, France
| | - Albrecht Fröhlich
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Ana Saintpierre
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Charlotte Decourt
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Florence Combes
- Univ. Grenoble Alpes, INSERM, CEA, UA13 BGE, CNRS, CEA, FR2048, 38000, Grenoble, France
| | - Homaira Nawabi
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Yohann Couté
- Univ. Grenoble Alpes, INSERM, CEA, UA13 BGE, CNRS, CEA, FR2048, 38000, Grenoble, France.
| | - Stephane Belin
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France.
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4
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Kueck NA, Hüwel S, Hoffmann A, Rentmeister A. Quantification of Propargylated RNA Nucleosides After Metabolic Labeling Via the Methylation Pathway. Chembiochem 2025; 26:e202400986. [PMID: 39993262 DOI: 10.1002/cbic.202400986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/19/2025] [Accepted: 02/24/2025] [Indexed: 02/26/2025]
Abstract
RNA modifications are involved in numerous biological processes and vary in different cell types. Methylation is the most widespread type of RNA modification and occurs via S-adenosyl-L-methionine (SAM). We recently developed a metabolic labeling approach based on intracellular formation of a clickable SAM analog (SeAdoYn) and demonstrated its use in mapping methyltransferase (MTase) target sites in mRNA from HeLa cells. Here we investigate how metabolic labeling via the clickable SAM analog modifies four different nucleosides in RNA of HEK293T in comparison to HeLa cells. We find that HEK293T cells retain higher cell viability upon feeding the clickable metabolic SAM precursor. In poly(A)+ RNA we find high Aprop/A levels (0.04 %) and in total RNA (but not poly(A)+ RNA) we detect prop3C, which had not been detected previously in HeLa cells. We discuss the findings in the context of data from the literature with respect to mRNA half-lives in cancer and non-cancer cell lines and suggest that CMTr2 is most likely responsible for the high Aprop level in poly(A)+ RNA.
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Affiliation(s)
- Nadine A Kueck
- University of Münster, Institute of Biochemistry, Corrensstr. 36, D-48149, Muenster, Germany
| | - Sabine Hüwel
- University of Münster, Institute of Biochemistry, Corrensstr. 36, D-48149, Muenster, Germany
| | - Arne Hoffmann
- Ludwig-Maximilians-University Munich, Department of Chemistry, Butenandtstr. 5-13, Haus F, D-81377, Munich, Germany
| | - Andrea Rentmeister
- Ludwig-Maximilians-University Munich, Department of Chemistry, Butenandtstr. 5-13, Haus F, D-81377, Munich, Germany
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5
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Pop NS, Dolt KS, Hohenstein P. Understanding developing kidneys and Wilms tumors one cell at a time. Curr Top Dev Biol 2025; 163:129-167. [PMID: 40254343 DOI: 10.1016/bs.ctdb.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2025]
Abstract
Single-cell sequencing-based techniques are revolutionizing all fields of biomedical sciences, including normal kidney development and how this is disturbed in the development of Wilms tumor. The many different techniques and the differences between them can obscure which technique is best used to answer which question. In this review we summarize the techniques currently available, discuss which have been used in kidney development or Wilms tumor context, and which techniques can or should be combined to maximize the increase in biological understanding we can get from them.
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Affiliation(s)
- Nine Solee Pop
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
| | - Karamjit Singh Dolt
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
| | - Peter Hohenstein
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
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6
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Gugnoni M, Kashyap MK, Wary KK, Ciarrocchi A. lncRNAs: the unexpected link between protein synthesis and cancer adaptation. Mol Cancer 2025; 24:38. [PMID: 39891197 PMCID: PMC11783725 DOI: 10.1186/s12943-025-02236-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/15/2025] [Indexed: 02/03/2025] Open
Abstract
Cancer progression relies on the ability of cells to adapt to challenging environments overcoming stresses and growth constraints. Such adaptation is a multifactorial process that depends on the rapid reorganization of many basic cellular mechanisms. Protein synthesis is often dysregulated in cancer, and translational reprogramming is emerging as a driving force of cancer adaptive plasticity. Long non-coding RNAs (lncRNAs) represent the main product of genome transcription. They outnumber mRNAs by an order of magnitude and their expression is regulated in an extremely specific manner depending on context, space and time. This heterogeneity is functional and allows lncRNAs to act as context-specific, fine-tuning controllers of gene expression. Multiple recent evidence underlines how, besides their consolidated role in transcription, lncRNAs are major players in translation control. Their capacity to establish multiple and highly dynamic interactions with proteins and other transcripts makes these molecules able to play a central role across all phases of protein synthesis. Even if through a myriad of different mechanisms, the action of these transcripts is dual. On one hand, by modulating the overall translation speed, lncRNAs participate in the process of metabolic adaptation of cancer cells under stress conditions. On the other hand, by prioritizing the synthesis of specific transcripts they help cancer cells to maintain high levels of essential oncogenes. In this review, we aim to discuss the most relevant evidence regarding the involvement of lncRNAs in translation regulation and to discuss how this specific function may affect cancer plasticity and resistance to stress. We also expect to provide one of the first collective perspectives on the way these transcripts modulate gene expression beyond transcription.
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Affiliation(s)
- Mila Gugnoni
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Manoj Kumar Kashyap
- Molecular Oncology Laboratory, Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon (Manesar), Gurugram, Haryana, India.
| | - Kishore K Wary
- Department of Pharmacology and Regenerative Medicine, University of Illinois, Chicago, IL, USA.
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
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7
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Bennett SA, Cobos SN, Fisher RMA, Son E, Frederic R, Segal R, Yousuf H, Chan K, Dansu DK, Torrente MP. Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model. J Fungi (Basel) 2025; 11:58. [PMID: 39852477 PMCID: PMC11766905 DOI: 10.3390/jof11010058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/02/2025] [Accepted: 01/09/2025] [Indexed: 01/26/2025] Open
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the FUS gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109-responsible for installing H3S10ph and H3K56ac-are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention.
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Affiliation(s)
- Seth A. Bennett
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
- Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
| | - Samantha N. Cobos
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
- Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
| | - Raven M. A. Fisher
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
- Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
| | - Elizaveta Son
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
| | - Rania Frederic
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
| | - Rianna Segal
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
| | - Huda Yousuf
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
| | - Kaitlyn Chan
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
| | - David K. Dansu
- Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
- Neuroscience Initiative, Advanced Science Research Center, CUNY, New York, NY 10031, USA
| | - Mariana P. Torrente
- Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA
- Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
- Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
- Ph.D. Program in Biology, The Graduate Center of the City University of New York, New York, NY 10016, USA
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8
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Soggia G, ElMaghloob Y, Boromangnaeva AK, Al Jord A. Mechanical Remodeling of Nuclear Biomolecular Condensates. Physiology (Bethesda) 2025; 40:0. [PMID: 39109673 DOI: 10.1152/physiol.00027.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/05/2024] [Accepted: 08/06/2024] [Indexed: 08/15/2024] Open
Abstract
Organism health relies on cell proliferation, migration, and differentiation. These universal processes depend on cytoplasmic reorganization driven notably by the cytoskeleton and its force-generating motors. Their activity generates forces that mechanically agitate the cell nucleus and its interior. New evidence from reproductive cell biology revealed that these cytoskeletal forces can be tuned to remodel nuclear membraneless compartments, known as biomolecular condensates, and regulate their RNA processing function for the success of subsequent cell division that is critical for fertility. Both cytoskeletal and nuclear condensate reorganization are common to numerous physiological and pathological contexts, raising the possibility that mechanical remodeling of nuclear condensates may be a much broader mechanism regulating their function. Here, we review this newfound mechanism of condensate remodeling and venture into the contexts of health and disease where it may be relevant, with a focus on reproduction, cancer, and premature aging.
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Affiliation(s)
- Giulia Soggia
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Yasmin ElMaghloob
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Systems Biology and Immunology Lab, Children's Cancer Hospital Egypt, Cairo, Egypt
| | | | - Adel Al Jord
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
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9
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Schaeffer J, Belin S. Axon regeneration: an issue of translation. C R Biol 2024; 347:249-258. [PMID: 39665232 DOI: 10.5802/crbiol.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 12/13/2024]
Abstract
In the mammalian central nervous system (CNS), adult neurons fail to regenerate spontaneously upon axon injury, which leads to a permanent and irreversible loss of neuronal functions. For more than 15 years, much effort was invested to unlock axon regrowth programs based on extensive transcriptomic characterization. However, it is now well described that mRNA and protein levels correlate only partially in cells, and that the transcription process (from DNA to mRNA) may not directly reflect protein expression. Conversely, the translation process (from mRNA to protein) provides an additional layer of gene regulation. This aspect has been overlooked in CNS regeneration. In this review, we discuss the limitations of transcriptomic approaches to promote CNS regeneration and we provide the rationale to investigate translational regulation in this context, and notably the regulatory role of the translational complex. Finally, we summarize our and others’ recent findings showing how variations in the translational complex composition regulate selective (mRNA-specific) translation, thereby controlling CNS axon regrowth.
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Aljardali MW, Kremer KM, Parker JE, Fleming E, Chen H, Lea JS, Kraus WL, Camacho CV. Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers. CANCER RESEARCH COMMUNICATIONS 2024; 4:1495-1504. [PMID: 38767454 PMCID: PMC11172406 DOI: 10.1158/2767-9764.crc-24-0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 04/03/2024] [Accepted: 05/14/2024] [Indexed: 05/22/2024]
Abstract
Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. SIGNIFICANCE Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.
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Affiliation(s)
- Marwa W. Aljardali
- Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kevin M. Kremer
- Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jessica E. Parker
- Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Elaine Fleming
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Hao Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jayanthi S. Lea
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - W. Lee Kraus
- Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Cristel V. Camacho
- Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
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11
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Hwang SP, Denicourt C. The impact of ribosome biogenesis in cancer: from proliferation to metastasis. NAR Cancer 2024; 6:zcae017. [PMID: 38633862 PMCID: PMC11023387 DOI: 10.1093/narcan/zcae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/23/2024] [Accepted: 03/26/2024] [Indexed: 04/19/2024] Open
Abstract
The dysregulation of ribosome biogenesis is a hallmark of cancer, facilitating the adaptation to altered translational demands essential for various aspects of tumor progression. This review explores the intricate interplay between ribosome biogenesis and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal the multifaceted roles of ribosomes, extending beyond protein factories to include regulatory functions in mRNA translation. Dysregulated ribosome biogenesis not only hampers precise control of global protein production and proliferation but also influences processes such as the maintenance of stem cell-like properties and epithelial-mesenchymal transition, contributing to cancer progression. Interference with ribosome biogenesis, notably through RNA Pol I inhibition, elicits a stress response marked by nucleolar integrity loss, and subsequent G1-cell cycle arrest or cell death. These findings suggest that cancer cells may rely on heightened RNA Pol I transcription, rendering ribosomal RNA synthesis a potential therapeutic vulnerability. The review further explores targeting ribosome biogenesis vulnerabilities as a promising strategy to disrupt global ribosome production, presenting therapeutic opportunities for cancer treatment.
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Affiliation(s)
- Sseu-Pei Hwang
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Catherine Denicourt
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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12
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López J, Blanco S. Exploring the role of ribosomal RNA modifications in cancer. Curr Opin Genet Dev 2024; 86:102204. [PMID: 38759459 DOI: 10.1016/j.gde.2024.102204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 04/05/2024] [Accepted: 05/03/2024] [Indexed: 05/19/2024]
Abstract
Recent advances have highlighted the significant roles of post-transcriptional modifications in rRNA in various cancers. Evidence suggests that dysregulation of rRNA modifications acts as a common denominator in cancer development, with alterations in these modifications conferring competitive advantages to cancer cells. Specifically, rRNA modifications modulate protein synthesis and favor the specialized translation of oncogenic programs, thereby contributing to the formation of a protumorigenic proteome in cancer cells. These findings reveal a novel regulatory layer mediated by changes in the deposition of rRNA chemical modifications. Moreover, inhibition of these modifications in vitro and in preclinical studies demonstrates potential therapeutic applications. The recurrence of altered rRNA modification patterns across different types of cancer underscores their importance in cancer progression, proposing them as potential biomarkers and novel therapeutic targets. This review will highlight the latest insights into how post-transcriptional rRNA modifications contribute to cancer progression and summarize the main developments and ongoing challenges in this research area.
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Affiliation(s)
- Judith López
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, 37007 Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, Spain. https://twitter.com/@judithlopezluis
| | - Sandra Blanco
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, 37007 Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, Spain.
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13
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Cui L, Zheng J, Lin Y, Lin P, Lu Y, Zheng Y, Guo B, Zhao X. Decoding the ribosome's hidden language: rRNA modifications as key players in cancer dynamics and targeted therapies. Clin Transl Med 2024; 14:e1705. [PMID: 38797935 PMCID: PMC11128715 DOI: 10.1002/ctm2.1705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 05/05/2024] [Accepted: 05/10/2024] [Indexed: 05/29/2024] Open
Abstract
Ribosomal RNA (rRNA) modifications, essential components of ribosome structure and function, significantly impact cellular proteomics and cancer biology. These chemical modifications transcend structural roles, critically shaping ribosome functionality and influencing cellular protein profiles. In this review, the mechanisms by which rRNA modifications regulate both rRNA functions and broader cellular physiological processes are critically discussed. Importantly, by altering the translational output, rRNA modifications can shift the cellular equilibrium towards oncogenesis, thus playing a key role in cancer development and progression. Moreover, a special focus is placed on the functions of mitochondrial rRNA modifications and their aberrant expression in cancer, an area with profound implications yet largely uncharted. Dysregulation in these modifications can lead to metabolic dysfunction and apoptosis resistance, hallmark traits of cancer cells. Furthermore, the current challenges and future perspectives in targeting rRNA modifications are highlighted as a therapeutic approach for cancer treatment. In conclusion, rRNA modifications represent a frontier in cancer research, offering novel insights and therapeutic possibilities. Understanding and harnessing these modifications can pave the way for breakthroughs in cancer treatment, potentially transforming the approach to combating this complex disease.
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Affiliation(s)
- Li Cui
- Stomatological Hospital, School of StomatologySouthern Medical UniversityGuangzhouGuangdongChina
- Division of Oral Biology and Medicine, School of DentistryUniversity of
California, Los AngelesLos AngelesUSA
| | - Jiarong Zheng
- Department of Dentistry, The First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Yunfan Lin
- Stomatological Hospital, School of StomatologySouthern Medical UniversityGuangzhouGuangdongChina
| | - Pei Lin
- Stomatological Hospital, School of StomatologySouthern Medical UniversityGuangzhouGuangdongChina
| | - Ye Lu
- Stomatological Hospital, School of StomatologySouthern Medical UniversityGuangzhouGuangdongChina
| | - Yucheng Zheng
- Stomatological Hospital, School of StomatologySouthern Medical UniversityGuangzhouGuangdongChina
| | - Bing Guo
- Department of Dentistry, The First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Xinyuan Zhao
- Stomatological Hospital, School of StomatologySouthern Medical UniversityGuangzhouGuangdongChina
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14
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Zheng C, Yao H, Lu L, Li H, Zhou L, He X, Xu X, Xia H, Ding S, Yang Y, Wang X, Wu M, Xue L, Chen S, Peng X, Cheng Z, Wang Y, He G, Fu S, Keller ET, Liu S, Jiang YZ, Deng X. Dysregulated Ribosome Biogenesis Is a Targetable Vulnerability in Triple-Negative Breast Cancer: MRPS27 as a Key Mediator of the Stemness-inhibitory Effect of Lovastatin. Int J Biol Sci 2024; 20:2130-2148. [PMID: 38617541 PMCID: PMC11008279 DOI: 10.7150/ijbs.94058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/16/2024] [Indexed: 04/16/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited effective therapeutic options readily available. We have previously demonstrated that lovastatin, an FDA-approved lipid-lowering drug, selectively inhibits the stemness properties of TNBC. However, the intracellular targets of lovastatin in TNBC remain largely unknown. Here, we unexpectedly uncovered ribosome biogenesis as the predominant pathway targeted by lovastatin in TNBC. Lovastatin induced the translocation of ribosome biogenesis-related proteins including nucleophosmin (NPM), nucleolar and coiled-body phosphoprotein 1 (NOLC1), and the ribosomal protein RPL3. Lovastatin also suppressed the transcript levels of rRNAs and increased the nuclear protein level and transcriptional activity of p53, a master mediator of nucleolar stress. A prognostic model generated from 10 ribosome biogenesis-related genes showed outstanding performance in predicting the survival of TNBC patients. Mitochondrial ribosomal protein S27 (MRPS27), the top-ranked risky model gene, was highly expressed and correlated with tumor stage and lymph node involvement in TNBC. Mechanistically, MRPS27 knockdown inhibited the stemness properties and the malignant phenotypes of TNBC. Overexpression of MRPS27 attenuated the stemness-inhibitory effect of lovastatin in TNBC cells. Our findings reveal that dysregulated ribosome biogenesis is a targetable vulnerability and targeting MRPS27 could be a novel therapeutic strategy for TNBC patients.
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Affiliation(s)
- Chanjuan Zheng
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Hui Yao
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Lu Lu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Hongqi Li
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Lei Zhou
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Xueyan He
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Xi Xu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Hongzhuo Xia
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Siyu Ding
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Yiyuan Yang
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Xinyu Wang
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Muyao Wu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Lian Xue
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Sisi Chen
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Xiaojun Peng
- Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development Area, Hangzhou, China
| | - Zhongyi Cheng
- Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development Area, Hangzhou, China
| | - Yian Wang
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Guangchun He
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Shujun Fu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Evan T. Keller
- Department of Urology and Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Yi-zhou Jiang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiyun Deng
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
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15
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Ma Y, Wang J, He X, Liu Y, Zhen S, An L, Yang Q, Niu F, Wang H, An B, Tai X, Yan Z, Wu C, Yang X, Liu X. Molecular mechanism of human ISG20L2 for the ITS1 cleavage in the processing of 18S precursor ribosomal RNA. Nucleic Acids Res 2024; 52:1878-1895. [PMID: 38153123 PMCID: PMC10899777 DOI: 10.1093/nar/gkad1210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/03/2023] [Accepted: 12/10/2023] [Indexed: 12/29/2023] Open
Abstract
The exonuclease ISG20L2 has been initially characterized for its role in the mammalian 5.8S rRNA 3' end maturation, specifically in the cleavage of ITS2 of 12S precursor ribosomal RNA (pre-rRNA). Here, we show that human ISG20L2 is also involved in 18S pre-rRNA maturation through removing the ITS1 region, and contributes to ribosomal biogenesis and cell proliferation. Furthermore, we determined the crystal structure of the ISG20L2 nuclease domain at 2.9 Å resolution. It exhibits the typical αβα fold of the DEDD 3'-5' exonuclease with a catalytic pocket located in the hollow near the center. The catalytic residues Asp183, Glu185, Asp267, His322 and Asp327 constitute the DEDDh motif in ISG20L2. The active pocket represents conformational flexibility in the absence of an RNA substrate. Using structural superposition and mutagenesis assay, we mapped RNA substrate binding residues in ISG20L2. Finally, cellular assays revealed that ISG20L2 is aberrantly up-regulated in colon adenocarcinoma and promotes colon cancer cell proliferation through regulating ribosome biogenesis. Together, these results reveal that ISG20L2 is a new enzymatic member for 18S pre-rRNA maturation, provide insights into the mechanism of ISG20L2 underlying pre-rRNA processing, and suggest that ISG20L2 is a potential therapeutic target for colon adenocarcinoma.
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Affiliation(s)
- Yinliang Ma
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Jiaxu Wang
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
- College of Life Sciences, State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Normal University, Xinxiang 453002 Henan, China
| | - Xingyi He
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Yuhang Liu
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Shuo Zhen
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Lina An
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Qian Yang
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Fumin Niu
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Hong Wang
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Boran An
- Affiliated Hospital of Hebei University, Hebei University, Baoding 071002 Hebei, China
| | - Xinyue Tai
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Zhenzhen Yan
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Chen Wu
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
| | - Xiaoyun Yang
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
- Department of Biology, Southern University of Science and Technology, Shenzhen 518055 Guangdong, China
| | - Xiuhua Liu
- College of Life Sciences, Hebei Innovation Center for Bioengineering and Biotechnology, Institute of Life Sciences and Green Development, Hebei University, Baoding 071002 Hebei, China
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16
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Huang YM, Hsu TY, Liu CY, Hsieh YC, Lai KY, Yang YW, Lo KY. Exploring the multifaceted impact of lanthanides on physiological pathways in human breast cancer cells. Toxicology 2024; 502:153731. [PMID: 38253231 DOI: 10.1016/j.tox.2024.153731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/09/2024] [Accepted: 01/17/2024] [Indexed: 01/24/2024]
Abstract
Lanthanum (La) and cerium (Ce), rare earth elements with physical properties similar to calcium (Ca), are generally considered non-toxic when used appropriately. However, their ions possess anti-tumor capabilities. This investigation explores the potential applications and mechanisms of LaCl3 or CeCl3 treatment in triple-negative breast cancer (TNBC) cell lines. TNBC, characterized by the absence of estrogen receptor (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is prone to early metastasis and resistant to hormone therapy. Our results demonstrate that La/Ce treatment reduces cell growth, and when combined with cisplatin, it synergistically inhibits cell growth and the PI3K/AKT pathway. La and Ce induce oxidative stress by disrupting mitochondrial function, leading to protein oxidation. Additionally, they interfere with protein homeostasis and induce nucleolar stress. Furthermore, disturbance in F-actin web formation impairs cell migration. This study delves into the mechanism by which calcium-like elements La and Ce inhibit breast cancer cell growth, shedding light on their interference in mitochondrial function, protein homeostasis, and cytoskeleton assembly.
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Affiliation(s)
- Yi-Ming Huang
- Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan, ROC
| | - Tsu-Yu Hsu
- Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan, ROC
| | - Ching-Yu Liu
- Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan, ROC
| | - Yu-Chen Hsieh
- Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan, ROC
| | - Kuan-Yun Lai
- Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan, ROC
| | - Ya-Wen Yang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, ROC.
| | - Kai-Yin Lo
- Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan, ROC.
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17
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Liu L, Liu Z, Liu Q, Wu W, Lin P, Liu X, Zhang Y, Wang D, Prager BC, Gimple RC, Yu J, Zhao W, Wu Q, Zhang W, Wu E, Chen X, Luo J, Rich JN, Xie Q, Jiang T, Chen R. LncRNA INHEG promotes glioma stem cell maintenance and tumorigenicity through regulating rRNA 2'-O-methylation. Nat Commun 2023; 14:7526. [PMID: 37980347 PMCID: PMC10657414 DOI: 10.1038/s41467-023-43113-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 10/31/2023] [Indexed: 11/20/2023] Open
Abstract
Glioblastoma (GBM) ranks among the most lethal of human cancers, containing glioma stem cells (GSCs) that display therapeutic resistance. Here, we report that the lncRNA INHEG is highly expressed in GSCs compared to differentiated glioma cells (DGCs) and promotes GSC self-renewal and tumorigenicity through control of rRNA 2'-O-methylation. INHEG induces the interaction between SUMO2 E3 ligase TAF15 and NOP58, a core component of snoRNP that guides rRNA methylation, to regulate NOP58 sumoylation and accelerate the C/D box snoRNP assembly. INHEG activation enhances rRNA 2'-O-methylation, thereby increasing the expression of oncogenic proteins including EGFR, IGF1R, CDK6 and PDGFRB in glioma cells. Taken together, this study identifies a lncRNA that connects snoRNP-guided rRNA 2'-O-methylation to upregulated protein translation in GSCs, supporting an axis for potential therapeutic targeting of gliomas.
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Affiliation(s)
- Lihui Liu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Ziyang Liu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Qinghua Liu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Wei Wu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Peng Lin
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 310024, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, China
| | - Xing Liu
- Beijing Neurosurgical Institute, 100050, Beijing, China
| | - Yuechuan Zhang
- Department of Department of Orthopedics, Peking Union Medical College Hospital, 100730, Beijing, China
| | - Dongpeng Wang
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Briana C Prager
- Department of Pathology, Case Western Reserve University, Cleveland, 44106, USA
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, 44195, USA
| | - Ryan C Gimple
- Department of Pathology, Case Western Reserve University, Cleveland, 44106, USA
| | - Jichuan Yu
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 310024, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, China
| | - Weixi Zhao
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 310024, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, China
| | - Qiulian Wu
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, 15261, USA
| | - Wei Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100050, Beijing, China
| | - Erzhong Wu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Xiaomin Chen
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Jianjun Luo
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Jeremy N Rich
- Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, 15261, USA.
| | - Qi Xie
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 310024, Hangzhou, China.
- Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, China.
| | - Tao Jiang
- Beijing Neurosurgical Institute, 100050, Beijing, China.
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100050, Beijing, China.
| | - Runsheng Chen
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
- University of Chinese Academy of Sciences, 100049, Beijing, China.
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18
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Wang Z, Ding J, Xiao Y, Xiao K, Su P, Dong Z, Zhang Y. Serum extracellular vesicles with NSD1 and FBXO7 mRNA as novel biomarkers for gastric cancer. Clin Biochem 2023; 120:110653. [PMID: 37742869 DOI: 10.1016/j.clinbiochem.2023.110653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/05/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND Messenger RNAs (mRNAs) in serum extracellular vesicles (EVs) are effective non-invasive biomarkers for various types of cancer, however, their role as biomarkers for gastric cancer is yet to be investigated. Therefore, the current study was designed to explore their potential as novel biomarkers for gastric cancer. METHODS The mRNAs in serum EVs from four patients with gastric cancer and four healthy controls were investigated. mRNAs in serum EVs were extracted for high-throughput RNA sequencing (RNA-seq). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict cancer-related genes. Candidate mRNAs were validated using reverse transcription-quantitative polymerase chain reaction. The diagnostic and prognostic values of mRNAs for gastric cancer were evaluated by receiver operating characteristic (ROC) curves and Kaplan-Meier analysis, respectively. RESULTS RNA-seq revealed 13,229 upregulated and 7,079 downregulated mRNAs in serum EVs. GO and KEGG analyses showed that certain mRNAs were associated with tumorigenesis and progression. From these, 10 were selected according to our criteria (|Fold Change| > 10, P < 0.05). NSD1 was upregulated and FBXO7 was downregulated in patients with gastric cancer compared with the healthy controls. The area under the ROC curves of these two mRNAs combined was 0.84, with a sensitivity of 78 % and a specificity of 92 %. NSD1 and FBXO7 were also associated with tumor size, distal metastasis, and TNM stage. Furthermore, NSD1 expression was strongly associated with prognosis, as revealed from our follow-up studies and online database analysis. However, FBXO7 was only significantly associated with prognosis in our follow-up data. CONCLUSIONS NSD1 and FBXO7 in serum EVs have important roles in gastric cancer and may be useful biomarkers for its diagnosis and prognosis.
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Affiliation(s)
- Zhen Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China
| | - Juan Ding
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China
| | - Yilei Xiao
- Department of Neurosurgery, Liaocheng People's Hospital, 67 Dongchangxi Road, Liaocheng 252000, Shandong, China
| | - Ke Xiao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China
| | - Ping Su
- National Administration of Health Data, Jinan 250000, Shandong, China
| | - Zhaogang Dong
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China.
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, 107 Wenhuaxi Road, Jinan 250012, Shandong, China.
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19
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Montel F. [Structural and mechanical plasticity of the nuclear pore]. Med Sci (Paris) 2023; 39:625-631. [PMID: 37695152 DOI: 10.1051/medsci/2023096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2023] Open
Abstract
The nuclear pore, which can be seen as the gateway to the cell nucleus, is central to many processes including gene regulation. It is a complex and dynamic structure composed of more than 30 proteins present in multiple copies that allows the selective and directional transport of RNA and proteins. As shown by recent studies, it is able to adapt its overall structure to the state of the cell. These results suggest that the structural and mechanical plasticity of the nuclear pore is important for its function but also in the development of cancer or viral infections.
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Affiliation(s)
- Fabien Montel
- Laboratoire de physique, CNRS UMR 5672, école normale supérieure de Lyon, université de Lyon, F-69342 Lyon, France
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20
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Costa PMDS, Sales SLA, Pinheiro DP, Pontes LQ, Maranhão SS, Pessoa CDÓ, Furtado GP, Furtado CLM. Epigenetic reprogramming in cancer: From diagnosis to treatment. Front Cell Dev Biol 2023; 11:1116805. [PMID: 36866275 PMCID: PMC9974167 DOI: 10.3389/fcell.2023.1116805] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 02/01/2023] [Indexed: 02/16/2023] Open
Abstract
Disruption of the epigenetic program of gene expression is a hallmark of cancer that initiates and propagates tumorigenesis. Altered DNA methylation, histone modifications and ncRNAs expression are a feature of cancer cells. The dynamic epigenetic changes during oncogenic transformation are related to tumor heterogeneity, unlimited self-renewal and multi-lineage differentiation. This stem cell-like state or the aberrant reprogramming of cancer stem cells is the major challenge in treatment and drug resistance. Given the reversible nature of epigenetic modifications, the ability to restore the cancer epigenome through the inhibition of the epigenetic modifiers is a promising therapy for cancer treatment, either as a monotherapy or in combination with other anticancer therapies, including immunotherapies. Herein, we highlighted the main epigenetic alterations, their potential as a biomarker for early diagnosis and the epigenetic therapies approved for cancer treatment.
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Affiliation(s)
- Pedro Mikael da Silva Costa
- Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceará, Fortaleza, Ceará, Brazil,Postgraduation Program in Biotechnology Northeastern Network of Biotechnology, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Sarah Leyenne Alves Sales
- Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceará, Fortaleza, Ceará, Brazil,Postgraduation Program in Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | | | - Larissa Queiroz Pontes
- Oswaldo Cruz Foundation, FIOCRUZ-Ceará, Sector of Biotechnology, Eusebio, Ceará, Brazil,Postgraduation Program in Biotechnology and Natural Resources, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Sarah Sant’Anna Maranhão
- Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Claudia do Ó. Pessoa
- Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceará, Fortaleza, Ceará, Brazil,Postgraduation Program in Biotechnology Northeastern Network of Biotechnology, Federal University of Ceará, Fortaleza, Ceará, Brazil,Postgraduation Program in Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Gilvan Pessoa Furtado
- Oswaldo Cruz Foundation, FIOCRUZ-Ceará, Sector of Biotechnology, Eusebio, Ceará, Brazil,Postgraduation Program in Biotechnology and Natural Resources, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Cristiana Libardi Miranda Furtado
- Drug Research and Development Center, Postgraduate Program in Translational Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil,Experimental Biology Center, University of Fortaleza, Fortaleza, Ceará, Brazil,*Correspondence: Cristiana Libardi Miranda Furtado,
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21
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Webster SF, Ghalei H. Maturation of small nucleolar RNAs: from production to function. RNA Biol 2023; 20:715-736. [PMID: 37796118 PMCID: PMC10557570 DOI: 10.1080/15476286.2023.2254540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2023] [Indexed: 10/06/2023] Open
Abstract
Small Nucleolar RNAs (snoRNAs) are an abundant group of non-coding RNAs with well-defined roles in ribosomal RNA processing, folding and chemical modification. Besides their classic roles in ribosome biogenesis, snoRNAs are also implicated in several other cellular activities including regulation of splicing, transcription, RNA editing, cellular trafficking, and miRNA-like functions. Mature snoRNAs must undergo a series of processing steps tightly regulated by transiently associating factors and coordinated with other cellular processes including transcription and splicing. In addition to their mature forms, snoRNAs can contribute to gene expression regulation through their derivatives and degradation products. Here, we review the current knowledge on mechanisms of snoRNA maturation, including the different pathways of processing, and the regulatory mechanisms that control snoRNA levels and complex assembly. We also discuss the significance of studying snoRNA maturation, highlight the gaps in the current knowledge and suggest directions for future research in this area.
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Affiliation(s)
- Sarah F. Webster
- Biochemistry, Cell, and Developmental Biology Graduate Program, Emory University, Atlanta, Georgia, USA
- Department of Biochemistry, Emory University, Atlanta, Georgia, USA
| | - Homa Ghalei
- Department of Biochemistry, Emory University, Atlanta, Georgia, USA
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22
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Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold. Nat Commun 2022; 13:6783. [PMID: 36351913 PMCID: PMC9646879 DOI: 10.1038/s41467-022-34610-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 10/31/2022] [Indexed: 11/11/2022] Open
Abstract
PELP1 (Proline-, Glutamic acid-, Leucine-rich protein 1) is a large scaffolding protein that functions in many cellular pathways including steroid receptor (SR) coactivation, heterochromatin maintenance, and ribosome biogenesis. PELP1 is a proto-oncogene whose expression is upregulated in many human cancers, but how the PELP1 scaffold coordinates its diverse cellular functions is poorly understood. Here we show that PELP1 serves as the central scaffold for the human Rix1 complex whose members include WDR18, TEX10, and SENP3. We reconstitute the mammalian Rix1 complex and identified a stable sub-complex comprised of the conserved PELP1 Rix1 domain and WDR18. We determine a 2.7 Å cryo-EM structure of the subcomplex revealing an interconnected tetrameric assembly and the architecture of PELP1's signaling motifs, including eleven LxxLL motifs previously implicated in SR signaling and coactivation of Estrogen Receptor alpha (ERα) mediated transcription. However, the structure shows that none of these motifs is in a conformation that would support SR binding. Together this work establishes that PELP1 scaffolds the Rix1 complex, and association with WDR18 may direct PELP1's activity away from SR coactivation.
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23
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Analysis of Expression Pattern of snoRNAs in Human Cells A549 Infected by Influenza A Virus. Int J Mol Sci 2022; 23:ijms232213666. [PMID: 36430145 PMCID: PMC9696202 DOI: 10.3390/ijms232213666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 10/20/2022] [Accepted: 10/29/2022] [Indexed: 11/09/2022] Open
Abstract
Small nucleolar RNAs (snoRNAs) are a highly expressed class of non-coding RNAs known for their role in guiding post-transcriptional modifications of ribosomal RNAs and small nuclear RNAs. Emerging studies suggest that snoRNAs are also implicated in regulating other vital cellular processes, such as pre-mRNA splicing and 3'-processing of mRNAs, and in the development of cancer and viral infections. There is an emerging body of evidence for specific snoRNA's involvement in the optimal replication of RNA viruses. In order to investigate the expression pattern of snoRNAs during influenza A viral infection, we performed RNA sequencing analysis of the A549 human cell line infected by influenza virus A/Puerto Rico/8/1934 (H1N1). We identified 66 that were upregulated and 55 that were downregulated in response to influenza A virus infection. The increased expression of most C/D-box snoRNAs was associated with elevated levels of 5'- and 3'-short RNAs derived from this snoRNA. Analysis of the poly(A)+ RNA sequencing data indicated that most of the differentially expressed snoRNAs synthesis was not correlated with the corresponding host genes expression. Furthermore, influenza A viral infection led to an imbalance in the expression of genes responsible for C/D small nucleolar ribonucleoprotein particles' biogenesis. In summary, our results indicate that the expression pattern of snoRNAs in A549 cells is significantly altered during influenza A viral infection.
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24
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Vitkin E, Singh A, Wise J, Ben-Elazar S, Yakhini Z, Golberg A. Nondestructive protein sampling with electroporation facilitates profiling of spatial differential protein expression in breast tumors in vivo. Sci Rep 2022; 12:15835. [PMID: 36151122 PMCID: PMC9508265 DOI: 10.1038/s41598-022-19984-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 09/07/2022] [Indexed: 11/26/2022] Open
Abstract
Excision tissue biopsy, while central to cancer treatment and precision medicine, presents risks to the patient and does not provide a sufficiently broad and faithful representation of the heterogeneity of solid tumors. Here we introduce e-biopsy—a novel concept for molecular profiling of solid tumors using molecular sampling with electroporation. As e-biopsy provides access to the molecular composition of a solid tumor by permeabilization of the cell membrane, it facilitates tumor diagnostics without tissue resection. Furthermore, thanks to its non tissue destructive characteristics, e-biopsy enables probing the solid tumor multiple times in several distinct locations in the same procedure, thereby enabling the spatial profiling of tumor molecular heterogeneity.We demonstrate e-biopsy in vivo, using the 4T1 breast cancer model in mice to assess its performance, as well as the inferred spatial differential protein expression. In particular, we show that proteomic profiles obtained via e-biopsy in vivo distinguish the tumors from healthy breast tissue and reflect spatial tumor differential protein expression. E-biopsy provides a completely new molecular sampling modality for solid tumors molecular cartography, providing information that potentially enables more rapid and sensitive detection at lesser risk, as well as more precise personalized medicine.
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Affiliation(s)
- Edward Vitkin
- School of Computer Science, Reichman University (IDC Herzliya), Herzliya, Israel
| | - Amrita Singh
- Porter School of Environment and Earth Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Julia Wise
- Porter School of Environment and Earth Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Shay Ben-Elazar
- School of Computer Science, Reichman University (IDC Herzliya), Herzliya, Israel
| | - Zohar Yakhini
- School of Computer Science, Reichman University (IDC Herzliya), Herzliya, Israel. .,Computer Science Faculty, Technion, Haifa, Israel.
| | - Alexander Golberg
- Porter School of Environment and Earth Sciences, Tel Aviv University, Tel Aviv, Israel.
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25
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Uncovering Oncogenic Mechanisms of Tumor Suppressor Genes in Breast Cancer Multi-Omics Data. Int J Mol Sci 2022; 23:ijms23179624. [PMID: 36077026 PMCID: PMC9455665 DOI: 10.3390/ijms23179624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/16/2022] [Accepted: 08/19/2022] [Indexed: 11/17/2022] Open
Abstract
Tumor suppressor genes (TSGs) are essential genes in the development of cancer. While they have many roles in normal cells, mutation and dysregulation of the TSGs result in aberrant molecular processes in cancer cells. Therefore, understanding TSGs and their roles in the oncogenic process is crucial for prevention and treatment of cancer. In this research, multi-omics breast cancer data were used to identify molecular mechanisms of TSGs in breast cancer. Differentially expressed genes and differentially coexpressed genes were identified in four large-scale transcriptomics data from public repositories and multi-omics data analyses of copy number, methylation and gene expression were performed. The results of the analyses were integrated using enrichment analysis and meta-analysis of a p-value summation method. The integrative analysis revealed that TSGs have a significant relationship with genes of gene ontology terms that are related to cell cycle, genome stability, RNA processing and metastasis, indicating the regulatory mechanisms of TSGs on cancer cells. The analysis frame and research results will provide valuable information for the further identification of TSGs in different types of cancers.
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26
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Thakur C, Carruthers NJ, Zhang Q, Xu L, Fu Y, Bi Z, Qiu Y, Zhang W, Wadgaonkar P, Almutairy B, Guo C, Stemmer PM, Chen F. Depletion of Mdig Changes Proteomic Profiling in Triple Negative Breast Cancer Cells. Biomedicines 2022; 10:2021. [PMID: 36009568 PMCID: PMC9405604 DOI: 10.3390/biomedicines10082021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Triple-negative breast cancers are highly aggressive with an overall poor prognosis and limited therapeutic options. We had previously investigated the role of mdig, an oncogenic gene induced by some environmental risk factors, on the pathogenesis of breast cancer. However, a comprehensive analysis of the proteomic profile affected by mdig in triple-negative breast cancer has not been determined yet. Using label-free bottom-up quantitative proteomics, we compared wildtype control and mdig knockout MDA-MB-231 cells and identified the proteins and pathways that are significantly altered with mdig deletion. A total of 904 differentially expressed (p < 0.005) proteins were identified in the KO cells. Approximately 30 pathways and networks linked to the pathogenicity of breast cancer were either up- or downregulated, such as EIF2 signaling, the unfolded protein response, and isoleucine degradation I. Ingenuity Pathway Analysis established that the differentially expressed proteins have relevant biological actions in cell growth, motility, and malignancy. These data provide the first insight into protein expression patterns in breast cancer associated with a complete disruption of the mdig gene and yielded substantial information on the key proteins, biological processes, and pathways modulated by mdig that contribute to breast cancer tumorigenicity and invasiveness.
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Affiliation(s)
- Chitra Thakur
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, 101 Nicolls Road, Stony Brook, NY 11794, USA
| | - Nicholas J. Carruthers
- Institute of Environmental Health Sciences, Wayne State University, 2309 Scott Hall, 540 E Canfield Ave, Detroit, MI 48202, USA
| | - Qian Zhang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Liping Xu
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Yao Fu
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Zhuoyue Bi
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Yiran Qiu
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Wenxuan Zhang
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Priya Wadgaonkar
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Bandar Almutairy
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
| | - Chunna Guo
- Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201, USA
| | - Paul M. Stemmer
- Institute of Environmental Health Sciences, Wayne State University, 2309 Scott Hall, 540 E Canfield Ave, Detroit, MI 48202, USA
| | - Fei Chen
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, The State University of New York, Lauterbur Drive, Stony Brook, NY 11794, USA
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, 101 Nicolls Road, Stony Brook, NY 11794, USA
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27
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Song X, He H, Zhang Y, Fan J, Wang L. Mechanisms of action of triptolide against colorectal cancer: insights from proteomic and phosphoproteomic analyses. Aging (Albany NY) 2022; 14:3084-3104. [PMID: 35366242 PMCID: PMC9037262 DOI: 10.18632/aging.203992] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/26/2022] [Indexed: 12/09/2022]
Abstract
Triptolide is a potent anti-inflammatory agent that also possesses anticancer activity, including against colorectal cancer (CRC), one of the most frequent cancers around the world. In order to clarify how triptolide may be effective against CRC, we analyzed the proteome and phosphoproteome of CRC cell line HCT116 after incubation for 48 h with the drug (40 nM) or vehicle. Tandem mass tagging led to the identification of 403 proteins whose levels increased and 559 whose levels decreased in the presence of triptolide. We also identified 3,110 sites in proteins that were phosphorylated at higher levels and 3,161 sites phosphorylated at lower levels in the presence of the drug. Analysis of these differentially expressed and/or phosphorylated proteins showed that they were enriched in pathways involving ribosome biogenesis, PI3K−Akt signaling, MAPK signaling, nucleic acid binding as well as other pathways. Protein–protein interactions were explored using the STRING database, and we identified nine protein modules and 15 hub proteins. Finally, we identified 57 motifs using motif analysis of phosphosites and found 16 motifs were experimentally verified for known protein kinases, while 41 appear to be novel. These findings may help clarify how triptolide works against CRC and may guide the development of novel treatments.
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Affiliation(s)
- Xinqiang Song
- College of Life Sciences, Xinyang Normal University, Xinyang 464000, China.,College of Medicine, Xinyang Normal University, Xinyang 464000, China
| | - Huanhuan He
- College of Life Sciences, Xinyang Normal University, Xinyang 464000, China
| | - Yu Zhang
- College of Life Sciences, Xinyang Normal University, Xinyang 464000, China
| | - Jinke Fan
- College of Life Sciences, Xinyang Normal University, Xinyang 464000, China
| | - Lei Wang
- College of Life Sciences, Xinyang Normal University, Xinyang 464000, China
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28
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Hahm ER, Singh SV. Gene Expression Changes by Diallyl Trisulfide Administration in Chemically-induced Mammary Tumors in Rats. J Cancer Prev 2022; 27:22-30. [PMID: 35419300 PMCID: PMC8984650 DOI: 10.15430/jcp.2022.27.1.22] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 11/06/2022] Open
Abstract
Diallyl trisulfide (DATS) was shown to be a potent inhibitor of luminal-type MCF-7 xenograft growth in vivo. The present study was conducted to determine the preventive effect of DATS administration using an N-methyl-N-nitrosourea (MNU)-induced rat mammary tumor model, which shares molecular resemblance to luminal-type human breast cancers. The DATS administration (50 mg/kg body weight, 5 times/week) was safe, but did not reduce mammary tumor latency, incidence, burden or multiplicity. Therefore, we conducted RNA-seq analysis using mammary tumors from control and DATS-treated rats (n = 3 for each group) to gain insights into lack of mammary tumor prevention by this phytochemical. The gene ontology and the Kyoto encyclopedia of genes and genomes pathway analyses of the RNA-seq data revealed upregulation of genes associated with ribosomes, translation, peptide biosynthetic/metabolic process, and oxidative phosphorylation but downregulation of genes associated with mitogen-activated protein kinases. A total of 33 genes associated with ribosomes were significantly upregulated by DATS treatment, including RPL11 and RPS14. Western blotting confirmed upregulation of RPL11 and neurofascin protein expression in mammary tumors from DATS-treated rats when compared to controls. A statistically significant increase in protein level of c-Jun N-terminal kinase 2 was also observed in tumors from DATS-treated rats when compared to controls. On the other hand, expression of complex I subunits NDUFV1 or NDUFS1 was not affected by DATS treatment. These results offer potential explanations for ineffectiveness of DATS in the chemically-induced rat mammary tumor model. Inhibitors of the proteins upregulated by DATS may be needed to improve chemopreventive efficacy of this phytochemical.
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Affiliation(s)
- Eun-Ryeong Hahm
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Shivendra V. Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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29
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Piel L, Rajan KS, Bussotti G, Varet H, Legendre R, Proux C, Douché T, Giai-Gianetto Q, Chaze T, Cokelaer T, Vojtkova B, Gordon-Bar N, Doniger T, Cohen-Chalamish S, Rengaraj P, Besse C, Boland A, Sadlova J, Deleuze JF, Matondo M, Unger R, Volf P, Michaeli S, Pescher P, Späth GF. Experimental evolution links post-transcriptional regulation to Leishmania fitness gain. PLoS Pathog 2022; 18:e1010375. [PMID: 35294501 PMCID: PMC8959184 DOI: 10.1371/journal.ppat.1010375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/28/2022] [Accepted: 02/15/2022] [Indexed: 12/30/2022] Open
Abstract
The protozoan parasite Leishmania donovani causes fatal human visceral leishmaniasis in absence of treatment. Genome instability has been recognized as a driver in Leishmania fitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting to in vitro culture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth in promastigote culture (fitness gain) impairing infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network associated with parasite fitness gain, with genome instability causing highly reproducible, gene dosage-independent and -dependent changes. Reduction of flagellar transcripts and increase in coding and non-coding RNAs implicated in ribosomal biogenesis and protein translation were not correlated to dosage changes of the corresponding genes, revealing a gene dosage-independent, post-transcriptional mechanism of regulation. In contrast, abundance of gene products implicated in post-transcriptional regulation itself correlated to corresponding gene dosage changes. Thus, RNA abundance during parasite adaptation is controled by direct and indirect gene dosage changes. We correlated differential expression of small nucleolar RNAs (snoRNAs) with changes in rRNA modification, providing first evidence that Leishmania fitness gain in culture may be controlled by post-transcriptional and epitranscriptomic regulation. Our findings propose a novel model for Leishmania fitness gain in culture, where differential regulation of mRNA stability and the generation of modified ribosomes may potentially filter deleterious from beneficial gene dosage effects and provide proteomic robustness to genetically heterogenous, adapting parasite populations. This model challenges the current, genome-centric approach to Leishmania epidemiology and identifies the Leishmania transcriptome and non-coding small RNome as potential novel sources for the discovery of biomarkers that may be associated with parasite phenotypic adaptation in clinical settings. Genome instability plays a central yet poorly understood role in human disease. Gene amplifications and deletions drive cancer development, microbial infection and therapeutic failure. The molecular mechanisms that harness the deleterious effects of genome instability to generate beneficial phenotypes in pathogenic systems are unknown. Here we study this important open question in the protozoan parasite Leishmania that causes devastating human diseases termed leishmaniases. Leishmania parasites lack transcriptional control and instead exploit genome instability to adapt to their host environment. Analyzing in vitro adaptation of hamster-derived parasites via gene copy number (genomic level) and gene expression changes (transcriptomic and proteomic levels), we show that these parasites likely exploit small nucleolar RNAs (snoRNAs) to mitigate toxic effects of genome instability by post-transcriptional regulation and the establishment of modified ribosomes. Our findings propose non-coding RNAs as potential novel biomarkers with diagnostic and prognostic value that may be linked to changes in parasite tissue tropism or drug susceptibility. This novel insight into Leishmania adaptation will be likely applicable to other fast evolving eukaryotic systems with unstable genomes, such as fungi or cancer cells.
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Affiliation(s)
- Laura Piel
- Institut Pasteur, Université de Paris, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
| | - K. Shanmugha Rajan
- The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
| | - Giovanni Bussotti
- Institut Pasteur, Université de Paris, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
- Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France
| | - Hugo Varet
- Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France
- Institut Pasteur, Biomics, Paris, France; Institut Pasteur, UTechS MSBio, Paris, France
| | - Rachel Legendre
- Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France
- Institut Pasteur, Biomics, Paris, France; Institut Pasteur, UTechS MSBio, Paris, France
| | - Caroline Proux
- Institut Pasteur, Biomics, Paris, France; Institut Pasteur, UTechS MSBio, Paris, France
| | - Thibaut Douché
- Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, Paris, France
| | - Quentin Giai-Gianetto
- Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France
- Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, Paris, France
| | - Thibault Chaze
- Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, Paris, France
| | - Thomas Cokelaer
- Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France
- Institut Pasteur, Biomics, Paris, France; Institut Pasteur, UTechS MSBio, Paris, France
| | - Barbora Vojtkova
- Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Nadav Gordon-Bar
- The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
| | - Tirza Doniger
- The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
| | - Smadar Cohen-Chalamish
- The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
| | - Praveenkumar Rengaraj
- The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
| | - Céline Besse
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France
| | - Anne Boland
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France
| | - Jovana Sadlova
- Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Jean-François Deleuze
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France
| | - Mariette Matondo
- Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, Paris, France
| | - Ron Unger
- The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
| | - Petr Volf
- Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Shulamit Michaeli
- The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
| | - Pascale Pescher
- Institut Pasteur, Université de Paris, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
- * E-mail: (PP); (GS)
| | - Gerald F. Späth
- Institut Pasteur, Université de Paris, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
- * E-mail: (PP); (GS)
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30
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Machine Learning analysis of high-grade serous ovarian cancer proteomic dataset reveals novel candidate biomarkers. Sci Rep 2022; 12:3041. [PMID: 35197484 PMCID: PMC8866540 DOI: 10.1038/s41598-022-06788-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 02/02/2022] [Indexed: 12/19/2022] Open
Abstract
Ovarian cancer is one of the most common gynecological malignancies, ranking third after cervical and uterine cancer. High-grade serous ovarian cancer (HGSOC) is one of the most aggressive subtype, and the late onset of its symptoms leads in most cases to an unfavourable prognosis. Current predictive algorithms used to estimate the risk of having Ovarian Cancer fail to provide sufficient sensitivity and specificity to be used widely in clinical practice. The use of additional biomarkers or parameters such as age or menopausal status to overcome these issues showed only weak improvements. It is necessary to identify novel molecular signatures and the development of new predictive algorithms able to support the diagnosis of HGSOC, and at the same time, deepen the understanding of this elusive disease, with the final goal of improving patient survival. Here, we apply a Machine Learning-based pipeline to an open-source HGSOC Proteomic dataset to develop a decision support system (DSS) that displayed high discerning ability on a dataset of HGSOC biopsies. The proposed DSS consists of a double-step feature selection and a decision tree, with the resulting output consisting of a combination of three highly discriminating proteins: TOP1, PDIA4, and OGN, that could be of interest for further clinical and experimental validation. Furthermore, we took advantage of the ranked list of proteins generated during the feature selection steps to perform a pathway analysis to provide a snapshot of the main deregulated pathways of HGSOC. The datasets used for this study are available in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) data portal (https://cptac-data-portal.georgetown.edu/).
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Faucher-Giguère L, Roy A, Deschamps-Francoeur G, Couture S, Nottingham RM, Lambowitz AM, Scott MS, Abou Elela S. High-grade ovarian cancer associated H/ACA snoRNAs promote cancer cell proliferation and survival. NAR Cancer 2022; 4:zcab050. [PMID: 35047824 PMCID: PMC8759569 DOI: 10.1093/narcan/zcab050] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/08/2021] [Accepted: 12/13/2021] [Indexed: 01/10/2023] Open
Abstract
Small nucleolar RNAs (snoRNAs) are an omnipresent class of non-coding RNAs involved in the modification and processing of ribosomal RNA (rRNA). As snoRNAs are required for ribosome production, the increase of which is a hallmark of cancer development, their expression would be expected to increase in proliferating cancer cells. However, assessing the nature and extent of snoRNAs' contribution to cancer biology has been largely limited by difficulties in detecting highly structured RNA. In this study, we used a dedicated midsize non-coding RNA (mncRNA) sensitive sequencing technique to accurately survey the snoRNA abundance in independently verified high-grade serous ovarian carcinoma (HGSC) and serous borderline tumour (SBT) tissues. The results identified SNORA81, SNORA19 and SNORA56 as an H/ACA snoRNA signature capable of discriminating between independent sets of HGSC, SBT and normal tissues. The expression of the signature SNORA81 correlates with the level of ribosomal RNA (rRNA) modification and its knockdown inhibits 28S rRNA pseudouridylation and accumulation leading to reduced cell proliferation and migration. Together our data indicate that specific subsets of H/ACA snoRNAs may promote tumour aggressiveness by inducing rRNA modification and synthesis.
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Affiliation(s)
| | | | | | | | | | | | | | - Sherif Abou Elela
- To whom correspondence should be addressed. Tel: +1 819 821 8000 (Ext 75275);
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32
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Therizols G, Bash-Imam Z, Panthu B, Machon C, Vincent A, Ripoll J, Nait-Slimane S, Chalabi-Dchar M, Gaucherot A, Garcia M, Laforêts F, Marcel V, Boubaker-Vitre J, Monet MA, Bouclier C, Vanbelle C, Souahlia G, Berthel E, Albaret MA, Mertani HC, Prudhomme M, Bertrand M, David A, Saurin JC, Bouvet P, Rivals E, Ohlmann T, Guitton J, Dalla Venezia N, Pannequin J, Catez F, Diaz JJ. Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance. Nat Commun 2022; 13:173. [PMID: 35013311 PMCID: PMC8748862 DOI: 10.1038/s41467-021-27847-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.
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MESH Headings
- Antimetabolites, Antineoplastic/pharmacology
- Cell Line, Tumor
- Cell Survival/drug effects
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- DNA Replication
- DNA, Neoplasm/genetics
- DNA, Neoplasm/metabolism
- Drug Resistance, Neoplasm/genetics
- Drug Tolerance/genetics
- Fluorouracil/pharmacology
- HCT116 Cells
- Halogenation
- Humans
- Protein Biosynthesis/drug effects
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Ribosomal/genetics
- RNA, Ribosomal/metabolism
- Receptor, IGF Type 1/agonists
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Ribosomes/drug effects
- Ribosomes/genetics
- Ribosomes/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Gabriel Therizols
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Zeina Bash-Imam
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Baptiste Panthu
- CIRI-Inserm U1111, Ecole Normale Supérieure de Lyon, Lyon, F-693643, France
- Inserm U1060, CARMEN, F-69310, Pierre Bénite, France
| | - Christelle Machon
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Laboratoire de chimie analytique, Faculté de pharmacie de Lyon, 8 avenue Rockefeller, F-69373, Lyon, France
- Laboratoire de biochimie et de pharmaco-toxicologie, Centre hospitalier Lyon-Sud - HCL, F-69495, Pierre Bénite, France
| | - Anne Vincent
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Julie Ripoll
- LIRMM, UMR 5506, University of Montpellier, CNRS, Montpellier, France
| | - Sophie Nait-Slimane
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Mounira Chalabi-Dchar
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Angéline Gaucherot
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Maxime Garcia
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Florian Laforêts
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Virginie Marcel
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | | | - Marie-Ambre Monet
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | | | - Christophe Vanbelle
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Guillaume Souahlia
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Elise Berthel
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Marie Alexandra Albaret
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Department of Translational Research and Innovation, Centre Léon Bérard, 69373, Lyon, France
| | - Hichem C Mertani
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | - Michel Prudhomme
- Department of Digestive Surgery, CHU Nimes, Univ Montpellier, Nimes, France
| | - Martin Bertrand
- Department of Digestive Surgery, CHU Nimes, Univ Montpellier, Nimes, France
| | - Alexandre David
- IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France
- IRMB-PPC, Univ Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Jean-Christophe Saurin
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Department of Endoscopy and Gastroenterology, Pavillon L, Edouard Herriot Hospital, Lyon, France
| | - Philippe Bouvet
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Ecole Normale Supérieure de Lyon, Lyon, France
| | - Eric Rivals
- LIRMM, UMR 5506, University of Montpellier, CNRS, Montpellier, France
- Institut Français de Bioinformatique, CNRS UMS 3601, Évry, France
| | - Théophile Ohlmann
- CIRI-Inserm U1111, Ecole Normale Supérieure de Lyon, Lyon, F-693643, France
| | - Jérôme Guitton
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
- Laboratoire de biochimie et de pharmaco-toxicologie, Centre hospitalier Lyon-Sud - HCL, F-69495, Pierre Bénite, France
- Laboratoire de toxicologie, Faculté de pharmacie de Lyon, Université de Lyon, 8 avenue Rockefeller, F-69373, Lyon, France
| | - Nicole Dalla Venezia
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
- Centre Léon Bérard, F-69008, Lyon, France
- Université de Lyon 1, F-69000, Lyon, France
| | | | - Frédéric Catez
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
- Centre Léon Bérard, F-69008, Lyon, France.
- Université de Lyon 1, F-69000, Lyon, France.
- Institut Convergence PLAsCAN, F-69373, Lyon, France.
| | - Jean-Jacques Diaz
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
- Centre Léon Bérard, F-69008, Lyon, France.
- Université de Lyon 1, F-69000, Lyon, France.
- Institut Convergence PLAsCAN, F-69373, Lyon, France.
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33
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Moraleva AA, Deryabin AS, Rubtsov YP, Rubtsova MP, Dontsova OA. Eukaryotic Ribosome Biogenesis: The 40S Subunit. Acta Naturae 2022; 14:14-30. [PMID: 35441050 PMCID: PMC9013438 DOI: 10.32607/actanaturae.11540] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 02/02/2022] [Indexed: 11/29/2022] Open
Abstract
The formation of eukaryotic ribosomes is a sequential process of ribosomal precursors maturation in the nucleolus, nucleoplasm, and cytoplasm. Hundreds of ribosomal biogenesis factors ensure the accurate processing and formation of the ribosomal RNAs' tertiary structure, and they interact with ribosomal proteins. Most of what we know about the ribosome assembly has been derived from yeast cell studies, and the mechanisms of ribosome biogenesis in eukaryotes are considered quite conservative. Although the main stages of ribosome biogenesis are similar across different groups of eukaryotes, this process in humans is much more complicated owing to the larger size of the ribosomes and pre-ribosomes and the emergence of regulatory pathways that affect their assembly and function. Many of the factors involved in the biogenesis of human ribosomes have been identified using genome-wide screening based on RNA interference. This review addresses the key aspects of yeast and human ribosome biogenesis, using the 40S subunit as an example. The mechanisms underlying these differences are still not well understood, because, unlike yeast, there are no effective methods for characterizing pre-ribosomal complexes in humans. Understanding the mechanisms of human ribosome assembly would have an incidence on a growing number of genetic diseases (ribosomopathies) caused by mutations in the genes encoding ribosomal proteins and ribosome biogenesis factors. In addition, there is evidence that ribosome assembly is regulated by oncogenic signaling pathways, and that defects in the ribosome biogenesis are linked to the activation of tumor suppressors.
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Affiliation(s)
- A. A. Moraleva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russia
| | - A. S. Deryabin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russia
| | - Yu. P. Rubtsov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russia
| | - M. P. Rubtsova
- Lomonosov Moscow State University, Faculty of Chemistry, Moscow, 119991 Russia
| | - O. A. Dontsova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russia
- Lomonosov Moscow State University, Faculty of Chemistry, Moscow, 119991 Russia
- Skolkovo Institute of Science and Technology, Moscow, 121205 Russia
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34
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De Vito R, Bellio R, Trippa L, Parmigiani G. Bayesian multistudy factor analysis for high-throughput biological data. Ann Appl Stat 2021. [DOI: 10.1214/21-aoas1456] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
| | - Ruggero Bellio
- Department of Economics and Statistics, University of Udine
| | - Lorenzo Trippa
- Department of Data Science, Dana Farber Cancer Institute
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35
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Pauli C, Kienhöfer M, Göllner S, Müller-Tidow C. Epitranscriptomic modifications in acute myeloid leukemia: m 6A and 2'- O-methylation as targets for novel therapeutic strategies. Biol Chem 2021; 402:1531-1546. [PMID: 34634841 DOI: 10.1515/hsz-2021-0286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 09/24/2021] [Indexed: 11/15/2022]
Abstract
Modifications of RNA commonly occur in all species. Multiple enzymes are involved as writers, erasers and readers of these modifications. Many RNA modifications or the respective enzymes are associated with human disease and especially cancer. Currently, the mechanisms how RNA modifications impact on a large number of intracellular processes are emerging and knowledge about the pathogenetic role of RNA modifications increases. In Acute Myeloid Leukemia (AML), the N6-methyladenosine (m6A) modification has emerged as an important modulator of leukemogenesis. The writer proteins METTL3 and METTL14 are both involved in AML pathogenesis and might be suitable therapeutic targets. Recently, close links between 2'-O-methylation (2'-O-me) of ribosomal RNA and leukemogenesis were discovered. The AML1-ETO oncofusion protein which specifically occurs in a subset of AML was found to depend on induction of snoRNAs and 2'-O-me for leukemogenesis. Also, NPM1, an important tumor suppressor in AML, was associated with altered snoRNAs and 2'-O-me. These findings point toward novel pathogenetic mechanisms and potential therapeutic interventions. The current knowledge and the implications are the topic of this review.
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Affiliation(s)
- Cornelius Pauli
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Michael Kienhöfer
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Stefanie Göllner
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Carsten Müller-Tidow
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL)-Heidelberg University Hospital, 69117 Heidelberg, Germany
- National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
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36
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Barros-Silva D, Klavert J, Jenster G, Jerónimo C, Lafontaine DLJ, Martens-Uzunova ES. The role of OncoSnoRNAs and Ribosomal RNA 2'-O-methylation in Cancer. RNA Biol 2021; 18:61-74. [PMID: 34775914 PMCID: PMC8677010 DOI: 10.1080/15476286.2021.1991167] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Ribosomes are essential nanomachines responsible for all protein production in cells. Ribosome biogenesis and function are energy costly processes, they are tightly regulated to match cellular needs. In cancer, major pathways that control ribosome biogenesis and function are often deregulated to ensure cell survival and to accommodate the continuous proliferation of tumour cells. Ribosomal RNAs (rRNAs) are abundantly modified with 2'-O-methylation (Nm, ribomethylation) being one of the most common modifications. In eukaryotic ribosomes, ribomethylation is performed by the methyltransferase Fibrillarin guided by box C/D small nucleolar RNAs (snoRNAs). Accumulating evidences indicate that snoRNA expression and ribosome methylation profiles are altered in cancer. Here we review our current knowledge on differential snoRNA expression and rRNA 2ʹ-O methylation in the context of human malignancies, and discuss the consequences and opportunities for cancer diagnostics, prognostics, and therapeutics.
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Affiliation(s)
- Daniela Barros-Silva
- Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.,Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), Porto, Portugal
| | - Jonathan Klavert
- Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Guido Jenster
- Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), Porto, Portugal.,Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (Icbas-up), Porto, Portugal
| | - Denis L J Lafontaine
- Rna Molecular Biology, Fonds De La Recherche Scientifique (F.r.s./fnrs), Université Libre De Bruxelles (Ulb), BioPark Campus, Gosselies, Belgium
| | - Elena S Martens-Uzunova
- Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
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37
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Jansson MD, Häfner SJ, Altinel K, Tehler D, Krogh N, Jakobsen E, Andersen JV, Andersen KL, Schoof EM, Ménard P, Nielsen H, Lund AH. Regulation of translation by site-specific ribosomal RNA methylation. Nat Struct Mol Biol 2021; 28:889-899. [PMID: 34759377 DOI: 10.1038/s41594-021-00669-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/03/2021] [Indexed: 11/09/2022]
Abstract
Ribosomes are complex ribozymes that interpret genetic information by translating messenger RNA (mRNA) into proteins. Natural variation in ribosome composition has been documented in several organisms and can arise from several different sources. A key question is whether specific control over ribosome heterogeneity represents a mechanism by which translation can be regulated. We used RiboMeth-seq to demonstrate that differential 2'-O-methylation of ribosomal RNA (rRNA) represents a considerable source of ribosome heterogeneity in human cells, and that modification levels at distinct sites can change dynamically in response to upstream signaling pathways, such as MYC oncogene expression. Ablation of one prominent methylation resulted in altered translation of select mRNAs and corresponding changes in cellular phenotypes. Thus, differential rRNA 2'-O-methylation can give rise to ribosomes with specialized function. This suggests a broader mechanism where the specific regulation of rRNA modification patterns fine tunes translation.
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Affiliation(s)
- Martin D Jansson
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
| | - Sophia J Häfner
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Kübra Altinel
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Disa Tehler
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai Krogh
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Emil Jakobsen
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Jens V Andersen
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Kasper L Andersen
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Erwin M Schoof
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Patrice Ménard
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Nielsen
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Anders H Lund
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
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38
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Del Toro N, Lessard F, Bouchard J, Mobasheri N, Guillon J, Igelmann S, Tardif S, Buffard T, Bourdeau V, Brakier-Gingras L, Ferbeyre G. Cellular Senescence limits Translational Readthrough. Biol Open 2021; 10:272574. [PMID: 34676390 PMCID: PMC8649927 DOI: 10.1242/bio.058688] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 10/14/2021] [Indexed: 11/20/2022] Open
Abstract
The origin and evolution of cancer cells is considered to be mainly fueled by DNA mutations. Although translation errors could also expand the cellular proteome, their role in cancer biology remains poorly understood. Tumor suppressors called caretakers block cancer initiation and progression by preventing DNA mutations and/or stimulating DNA repair. If translational errors contribute to tumorigenesis, then caretaker genes should prevent such errors in normal cells in response to oncogenic stimuli. Here, we show that the process of cellular senescence induced by oncogenes, tumor suppressors or chemotherapeutic drugs is associated with a reduction in translational readthrough (TR) measured using reporters containing termination codons withing the context of both normal translation termination or programmed TR. Senescence reduced both basal TR and TR stimulated by aminoglycosides. Mechanistically, the reduction of TR during senescence is controlled by the RB tumor suppressor pathway. Cells that escape from cellular senescence either induced by oncogenes or chemotherapy have an increased TR. Also, breast cancer cells that escape from therapy-induced senescence express high levels of AGO1x, a TR isoform of AGO1 linked to breast cancer progression. We propose that senescence and the RB pathway reduce TR limiting proteome diversity and the expression of TR proteins required for cancer cell proliferation. Summary: We report that senescence and the RB pathway reduce translational readthrough (TR) limiting proteome diversity and the expression of TR proteins such as Ago1X required for cancer cell proliferation.
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Affiliation(s)
- Neylen Del Toro
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada
| | - Frédéric Lessard
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada
| | - Jacob Bouchard
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada
| | - Nasrin Mobasheri
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada
| | - Jordan Guillon
- CRCHUM, 900 Saint-Denis, bureau R10.432, Montréal, Québec, H2X 0A9, Canada
| | - Sebastian Igelmann
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada.,CRCHUM, 900 Saint-Denis, bureau R10.432, Montréal, Québec, H2X 0A9, Canada
| | - Sarah Tardif
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada
| | - Tony Buffard
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada
| | - Véronique Bourdeau
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada
| | - Léa Brakier-Gingras
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada
| | - Gerardo Ferbeyre
- Département de Biochimie et Médecine Moléculaire, Université de Montréal C.P. 6128, Succ. Centre-Ville, Montréal, Québec, H3C 3J7, Canada.,CRCHUM, 900 Saint-Denis, bureau R10.432, Montréal, Québec, H2X 0A9, Canada
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39
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Dannfald A, Favory JJ, Deragon JM. Variations in transfer and ribosomal RNA epitranscriptomic status can adapt eukaryote translation to changing physiological and environmental conditions. RNA Biol 2021; 18:4-18. [PMID: 34159889 PMCID: PMC8677040 DOI: 10.1080/15476286.2021.1931756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 01/27/2023] Open
Abstract
The timely reprogramming of gene expression in response to internal and external cues is essential to eukaryote development and acclimation to changing environments. Chemically modifying molecular receptors and transducers of these signals is one way to efficiently induce proper physiological responses. Post-translation modifications, regulating protein biological activities, are central to many well-known signal-responding pathways. Recently, messenger RNA (mRNA) chemical (i.e. epitranscriptomic) modifications were also shown to play a key role in these processes. In contrast, transfer RNA (tRNA) and ribosomal RNA (rRNA) chemical modifications, although critical for optimal function of the translation apparatus, and much more diverse and quantitatively important compared to mRNA modifications, were until recently considered as mainly static chemical decorations. We present here recent observations that are challenging this view and supporting the hypothesis that tRNA and rRNA modifications dynamically respond to various cell and environmental conditions and contribute to adapt translation to these conditions.
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Affiliation(s)
- Arnaud Dannfald
- CNRS LGDP-UMR5096, Pepignan, France
- Université de Perpignan via Domitia, Perpignan, France
| | - Jean-Jacques Favory
- CNRS LGDP-UMR5096, Pepignan, France
- Université de Perpignan via Domitia, Perpignan, France
| | - Jean-Marc Deragon
- CNRS LGDP-UMR5096, Pepignan, France
- Université de Perpignan via Domitia, Perpignan, France
- Institut Universitaire de France, Paris, France
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40
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Kumari K, Groza P, Aguilo F. Regulatory roles of RNA modifications in breast cancer. NAR Cancer 2021; 3:zcab036. [PMID: 34541538 PMCID: PMC8445368 DOI: 10.1093/narcan/zcab036] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/07/2021] [Accepted: 08/25/2021] [Indexed: 12/14/2022] Open
Abstract
Collectively referred to as the epitranscriptome, RNA modifications play important roles in gene expression control regulating relevant cellular processes. In the last few decades, growing numbers of RNA modifications have been identified not only in abundant ribosomal (rRNA) and transfer RNA (tRNA) but also in messenger RNA (mRNA). In addition, many writers, erasers and readers that dynamically regulate the chemical marks have also been characterized. Correct deposition of RNA modifications is prerequisite for cellular homeostasis, and its alteration results in aberrant transcriptional programs that dictate human disease, including breast cancer, the most frequent female malignancy, and the leading cause of cancer-related death in women. In this review, we emphasize the major RNA modifications that are present in tRNA, rRNA and mRNA. We have categorized breast cancer-associated chemical marks and summarize their contribution to breast tumorigenesis. In addition, we describe less abundant tRNA modifications with related pathways implicated in breast cancer. Finally, we discuss current limitations and perspectives on epitranscriptomics for use in therapeutic strategies against breast and other cancers.
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Affiliation(s)
- Kanchan Kumari
- Department of Molecular Biology, Umeå University, SE-901 85 Umeå, Sweden
| | - Paula Groza
- Department of Molecular Biology, Umeå University, SE-901 85 Umeå, Sweden
| | - Francesca Aguilo
- Department of Molecular Biology, Umeå University, SE-901 85 Umeå, Sweden
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41
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Chalabi-Dchar M, Fenouil T, Machon C, Vincent A, Catez F, Marcel V, Mertani HC, Saurin JC, Bouvet P, Guitton J, Venezia ND, Diaz JJ. A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate. NAR Cancer 2021; 3:zcab032. [PMID: 34409299 PMCID: PMC8364333 DOI: 10.1093/narcan/zcab032] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/01/2021] [Accepted: 08/09/2021] [Indexed: 12/24/2022] Open
Abstract
5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse.
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Affiliation(s)
- Mounira Chalabi-Dchar
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Tanguy Fenouil
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Christelle Machon
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Anne Vincent
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Frédéric Catez
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Virginie Marcel
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Hichem C Mertani
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Jean-Christophe Saurin
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Philippe Bouvet
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Jérôme Guitton
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Nicole Dalla Venezia
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
| | - Jean-Jacques Diaz
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, F-69373 Lyon Cedex 08, France
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Jaafar M, Paraqindes H, Gabut M, Diaz JJ, Marcel V, Durand S. 2'O-Ribose Methylation of Ribosomal RNAs: Natural Diversity in Living Organisms, Biological Processes, and Diseases. Cells 2021; 10:1948. [PMID: 34440717 PMCID: PMC8393311 DOI: 10.3390/cells10081948] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 01/21/2023] Open
Abstract
Recent findings suggest that ribosomes, the translational machineries, can display a distinct composition depending on physio-pathological contexts. Thanks to outstanding technological breakthroughs, many studies have reported that variations of rRNA modifications, and more particularly the most abundant rRNA chemical modification, the rRNA 2'O-ribose methylation (2'Ome), intrinsically occur in many organisms. In the last 5 years, accumulating reports have illustrated that rRNA 2'Ome varies in human cell lines but also in living organisms (yeast, plant, zebrafish, mouse, human) during development and diseases. These rRNA 2'Ome variations occur either within a single cell line, organ, or patient's sample (i.e., intra-variability) or between at least two biological conditions (i.e., inter-variability). Thus, the ribosomes can tolerate the absence of 2'Ome at some specific positions. These observations question whether variations in rRNA 2'Ome could provide ribosomes with particular translational regulatory activities and functional specializations. Here, we compile recent studies supporting the heterogeneity of ribosome composition at rRNA 2'Ome level and provide an overview of the natural diversity in rRNA 2'Ome that has been reported up to now throughout the kingdom of life. Moreover, we discuss the little evidence that suggests that variations of rRNA 2'Ome can effectively impact the ribosome activity and contribute to the etiology of some human diseases.
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Affiliation(s)
| | | | | | | | - Virginie Marcel
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, CEDEX 08, F-69373 Lyon, France; (M.J.); (H.P.); (M.G.); (J.-J.D.)
| | - Sébastien Durand
- Inserm U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, CEDEX 08, F-69373 Lyon, France; (M.J.); (H.P.); (M.G.); (J.-J.D.)
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43
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Baptista B, Riscado M, Queiroz J, Pichon C, Sousa F. Non-coding RNAs: Emerging from the discovery to therapeutic applications. Biochem Pharmacol 2021. [DOI: 10.1016/j.bcp.2021.114469 order by 22025--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2022]
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44
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Quantitative profiling of pseudouridylation dynamics in native RNAs with nanopore sequencing. Nat Biotechnol 2021; 39:1278-1291. [PMID: 33986546 DOI: 10.1038/s41587-021-00915-6] [Citation(s) in RCA: 182] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 04/06/2021] [Indexed: 01/23/2023]
Abstract
Nanopore RNA sequencing shows promise as a method for discriminating and identifying different RNA modifications in native RNA. Expanding on the ability of nanopore sequencing to detect N6-methyladenosine, we show that other modifications, in particular pseudouridine (Ψ) and 2'-O-methylation (Nm), also result in characteristic base-calling 'error' signatures in the nanopore data. Focusing on Ψ modification sites, we detected known and uncovered previously unreported Ψ sites in mRNAs, non-coding RNAs and rRNAs, including a Pus4-dependent Ψ modification in yeast mitochondrial rRNA. To explore the dynamics of pseudouridylation, we treated yeast cells with oxidative, cold and heat stresses and detected heat-sensitive Ψ-modified sites in small nuclear RNAs, small nucleolar RNAs and mRNAs. Finally, we developed a software, nanoRMS, that estimates per-site modification stoichiometries by identifying single-molecule reads with altered current intensity and trace profiles. This work demonstrates that Nm and Ψ RNA modifications can be detected in cellular RNAs and that their modification stoichiometry can be quantified by nanopore sequencing of native RNA.
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45
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Baldini L, Charpentier B, Labialle S. Emerging Data on the Diversity of Molecular Mechanisms Involving C/D snoRNAs. Noncoding RNA 2021; 7:ncrna7020030. [PMID: 34066559 PMCID: PMC8162545 DOI: 10.3390/ncrna7020030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022] Open
Abstract
Box C/D small nucleolar RNAs (C/D snoRNAs) represent an ancient family of small non-coding RNAs that are classically viewed as housekeeping guides for the 2′-O-methylation of ribosomal RNA in Archaea and Eukaryotes. However, an extensive set of studies now argues that they are involved in mechanisms that go well beyond this function. Here, we present these pieces of evidence in light of the current comprehension of the molecular mechanisms that control C/D snoRNA expression and function. From this inventory emerges that an accurate description of these activities at a molecular level is required to let the snoRNA field enter in a second age of maturity.
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Affiliation(s)
| | - Bruno Charpentier
- Correspondence: (B.C.); (S.L.); Tel.: +33-3-72-74-66-27 (B.C.); +33-3-72-74-66-51 (S.L.)
| | - Stéphane Labialle
- Correspondence: (B.C.); (S.L.); Tel.: +33-3-72-74-66-27 (B.C.); +33-3-72-74-66-51 (S.L.)
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46
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Ribosomal RNA Transcription Regulation in Breast Cancer. Genes (Basel) 2021; 12:genes12040502. [PMID: 33805424 PMCID: PMC8066022 DOI: 10.3390/genes12040502] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/24/2022] Open
Abstract
Ribosome biogenesis is a complex process that is responsible for the formation of ribosomes and ultimately global protein synthesis. The first step in this process is the synthesis of the ribosomal RNA in the nucleolus, transcribed by RNA Polymerase I. Historically, abnormal nucleolar structure is indicative of poor cancer prognoses. In recent years, it has been shown that ribosome biogenesis, and rDNA transcription in particular, is dysregulated in cancer cells. Coupled with advancements in screening technology that allowed for the discovery of novel drugs targeting RNA Polymerase I, this transcriptional machinery is an increasingly viable target for cancer therapies. In this review, we discuss ribosome biogenesis in breast cancer and the different cellular pathways involved. Moreover, we discuss current therapeutics that have been found to affect rDNA transcription and more novel drugs that target rDNA transcription machinery as a promising avenue for breast cancer treatment.
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47
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Baptista B, Riscado M, Queiroz JA, Pichon C, Sousa F. Non-coding RNAs: Emerging from the discovery to therapeutic applications. Biochem Pharmacol 2021; 189:114469. [PMID: 33577888 DOI: 10.1016/j.bcp.2021.114469] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/03/2021] [Accepted: 02/04/2021] [Indexed: 02/06/2023]
Abstract
The knowledge about non-coding RNAs (ncRNAs) is rapidly increasing with new data continuously emerging, regarding their diverse types, applications, and roles. Particular attention has been given to ncRNA with regulatory functions, which may have a critical role both in biological and pathological conditions. As a result of the diversity of ncRNAs and their ubiquitous involvement in several biologic processes, ncRNA started to be considered in the biomedical field, with immense potential to be exploited either as biomarkers or as therapeutic agents in certain pathologies. Indeed, ncRNA-based therapeutics have been proposed in many disorders and some even reached clinical trials. However, to prepare an RNA product suitable for pharmacological applications, certain criteria must be fulfilled, and it has to be guaranteed RNA purity, stability, and bioactivity. So, in this review, the different types of ncRNAs are identified and characterized, by describing their biogenesis, functions, and applications. A perspective on the main challenges and innovative approaches for the future and broad therapeutic application of RNA is also presented.
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Affiliation(s)
- B Baptista
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - M Riscado
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - J A Queiroz
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - C Pichon
- Centre de Biophysique Moléculaire (CBM), UPR 4301 CNRS & University of Orléans Orléans, France
| | - F Sousa
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal.
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48
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Wang J, Wang F, Li Q, Wang Q, Li J, Wang Y, Sun J, Lu D, Zhou H, Li S, Ma S, Xie J, Wen T. Proteomics and molecular network analyses reveal that the interaction between the TAT-DCF1 peptide and TAF6 induces an antitumor effect in glioma cells. Mol Omics 2021; 16:73-82. [PMID: 31899468 DOI: 10.1039/c9mo00068b] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Glioblastoma is the most lethal brain cancer in adults. Despite advances in surgical techniques, radiotherapy, and chemotherapy, their therapeutic effect is far from significant, since the detailed underlying pathological mechanism of this cancer is unclear. The establishment of molecular interaction networks has laid the foundation for the exploration of these mechanisms with a view to improving therapy for glioblastoma. In the present study, to further explore the cellular role of DCF1 (dendritic cell-derived factor 1), the proteins bound to TAT-DCF1 (transactivator of transcription-dendritic cell-derived factor 1) were identified, and biosystem analysis was employed. Functional enrichment analyses indicate that TAT-DCF1 induced important biological changes in U251 cells. Furthermore, the established molecular interaction networks indicated that TAT-DCF1 directly interacted with TAF6 in glioma cells and with UBC in HEK293T (human embryonic kidney 293T) cells. In addition, further biological experiments demonstrate that TAT-DCF1 induced the activation of the RPS27A/TOP2A/HMGB2/BCL-2 signaling pathway via interaction with TAF6 in U251 cells. Taken together, these findings suggest that the TAT-DCF1 peptide possesses great potential for the development of glioblastoma therapy through the interaction with TAF6-related pathways and provides further theoretic evidence for the mechanisms underlying the antitumor effects of TAT-DCF1.
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Affiliation(s)
- Jiao Wang
- Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University, 99 Shang Da Road, Shanghai 200444, China.
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49
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Nombela P, Miguel-López B, Blanco S. The role of m 6A, m 5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities. Mol Cancer 2021; 20:18. [PMID: 33461542 PMCID: PMC7812662 DOI: 10.1186/s12943-020-01263-w] [Citation(s) in RCA: 322] [Impact Index Per Article: 80.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 09/24/2020] [Indexed: 12/12/2022] Open
Abstract
RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N6-methyladenosine (m6A), 5-methylcytosine (m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.
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Affiliation(s)
- Paz Nombela
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, 37007, Salamanca, Spain
| | - Borja Miguel-López
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, 37007, Salamanca, Spain
| | - Sandra Blanco
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, 37007, Salamanca, Spain. .,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007, Salamanca, Spain.
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50
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Metge BJ, Kammerud SC, Pruitt HC, Shevde LA, Samant RS. Hypoxia re-programs 2'-O-Me modifications on ribosomal RNA. iScience 2020; 24:102010. [PMID: 33490918 PMCID: PMC7811136 DOI: 10.1016/j.isci.2020.102010] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 12/07/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
Hypoxia is one of the critical stressors encountered by various cells of the human body under diverse pathophysiologic conditions including cancer and has profound impacts on several metabolic and physiologic processes. Hypoxia prompts internal ribosome entry site (IRES)-mediated translation of key genes, such as VEGF, that are vital for tumor progression. Here, we describe that hypoxia remarkably upregulates RNA Polymerase I activity. We discovered that in hypoxia, rRNA shows a different methylation pattern compared to normoxia. Heterogeneity in ribosomes due to the diversity of ribosomal RNA and protein composition has been postulated to generate “specialized ribosomes” that differentially regulate translation. We find that in hypoxia, a sub-set of differentially methylated ribosomes recognizes the VEGF-C IRES, suggesting that ribosomal heterogeneity allows for altered ribosomal functions in hypoxia.
Chronic hypoxia stimulates RNA Pol I activity In hypoxia, a pool of specialized rRNA translates VEGFC IRES Hypoxia changes 2′-O-Me modification - epitranscriptomic marks on rRNA
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Affiliation(s)
- Brandon J Metge
- Department of Pathology, University of Alabama at Birmingham, WTI 320E 1824 6 Avenue South, Birmingham, AL 35233, USA
| | - Sarah C Kammerud
- Department of Pathology, University of Alabama at Birmingham, WTI 320E 1824 6 Avenue South, Birmingham, AL 35233, USA
| | - Hawley C Pruitt
- Department of Pathology, University of Alabama at Birmingham, WTI 320E 1824 6 Avenue South, Birmingham, AL 35233, USA
| | - Lalita A Shevde
- Department of Pathology, University of Alabama at Birmingham, WTI 320E 1824 6 Avenue South, Birmingham, AL 35233, USA.,O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rajeev S Samant
- Department of Pathology, University of Alabama at Birmingham, WTI 320E 1824 6 Avenue South, Birmingham, AL 35233, USA.,Birmingham VA Medical Center, Birmingham, AL, USA
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