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Ashley CN, Broni E, Pena-Martinez M, Wood CM, Kwofie SK, Miller WA. Computer-Aided Discovery of Natural Compounds Targeting the ADAR2 dsRBD2-RNA Interface and Computational Modeling of Full-Length ADAR2 Protein Structure. Int J Mol Sci 2025; 26:4075. [PMID: 40362314 PMCID: PMC12072074 DOI: 10.3390/ijms26094075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/15/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
Mesothelioma is a rare and aggressive cancer linked to asbestos exposure and characterized by rapid metastasis and poor prognosis. Inhibition of adenosine deaminase acting on dsRNA 2 (ADAR2) RNA binding but not ADAR2 editing has shown antitumor effects in mesothelioma. Natural compounds from the Traditional Chinese Medicine (TCM) database were docked to the RNA-binding interface of ADAR2's second dsRNA binding domain (dsRBD2), and their drug-likeness and predicted safety were assessed. Eight ligands (ZINC000085597263, ZINC000085633079, ZINC000014649947, ZINC000034512861, ZINC000070454124, ZINC000085594944, ZINC000085633008, and ZINC000095909822) showed high binding affinity to dsRBD2 from molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. Protein-ligand interactions were analyzed to identify key residues contributing to these binding affinities. Molecular dynamics (MD) simulations of dsRBD-ligand-RNA complexes revealed that four compounds (ZINC000085597263, ZINC000085633079, ZINC000014649947, and ZINC000034512861) had negative binding affinities to dsRBD2 in the presence of the RNA substrate GluR-2. Key residues, including Val164, Met165, Lys209, and Lys212, were crucial for ligand binding, even with RNA present, suggesting these compounds could inhibit dsRBD2's RNA-binding function. The predicted biological activities of these compounds indicate potential anticancer properties, particularly for the treatment of mesothelioma. These compounds are structurally similar to known anti-mesothelioma agents or anticancer drugs, highlighting their therapeutic potential. Current mesothelioma treatments are limited. Optimization of these compounds, alone or in combination with current therapeutics, has potential for mesothelioma treatment. Additionally, five high-quality full-length ADAR2 models were developed. These models provide insights into ADAR2 function, mutation impacts, and potential areas for protein engineering to enhance stability, RNA-binding specificity, or protein interactions, particularly concerning dimerization or complex formation with other proteins and RNAs.
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Affiliation(s)
- Carolyn N. Ashley
- Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA; (C.N.A.); (E.B.)
| | - Emmanuel Broni
- Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA; (C.N.A.); (E.B.)
| | - Michelle Pena-Martinez
- Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA; (C.N.A.); (E.B.)
| | - Chanyah M. Wood
- Department of Molecular Pharmacology & Neuroscience, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA
| | - Samuel K. Kwofie
- Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra LG 77, Ghana;
| | - Whelton A. Miller
- Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA; (C.N.A.); (E.B.)
- Department of Molecular Pharmacology & Neuroscience, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA
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Modestov A, Buzdin A, Suntsova M. Unveiling RNA Editing by ADAR and APOBEC Protein Gene Families. FRONT BIOSCI-LANDMRK 2025; 30:26298. [PMID: 40302320 DOI: 10.31083/fbl26298] [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: 08/27/2024] [Revised: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 05/02/2025]
Abstract
RNA editing is a crucial post-transcriptional modification that alters the transcriptome and proteome and affects many cellular processes, including splicing, microRNA specificity, stability of RNA molecules, and protein structure. Enzymes from the adenosine deaminase acting on RNA (ADAR) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) protein families mediate RNA editing and can alter a variety of non-coding and coding RNAs, including all regions of mRNA molecules, leading to tumor development and progression. This review provides novel insights into the potential use of RNA editing parameters, such as editing levels, expression of ADAR and APOBEC genes, and specifically edited genes, as biomarkers for cancer progression, distinguishing it from previous studies that focused on isolated aspects of RNA editing mechanisms. The methodological section offers clues to accelerate high-throughput analysis of RNA or DNA sequencing data for the identification of RNA editing events.
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Affiliation(s)
- Alexander Modestov
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow, Russia
| | - Anton Buzdin
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
- PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium
| | - Maria Suntsova
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
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Ranga S, Yadav R, Chauhan M, Chhabra R, Ahuja P, Balhara N. Modifications of RNA in cancer: a comprehensive review. Mol Biol Rep 2025; 52:321. [PMID: 40095076 DOI: 10.1007/s11033-025-10419-0] [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: 12/27/2024] [Accepted: 03/06/2025] [Indexed: 03/19/2025]
Abstract
RNA modifications play essential roles in post-transcriptional gene regulation and have emerged as significant contributors to cancer biology. Major chemical modifications of RNA include N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), pseudouridine (ψ), and N7-methylguanosine (m7G). Their dynamic regulation highlights their roles in gene expression modulation, RNA stability, and translation. Advanced high-throughput detection methods, ranging from liquid chromatography-mass spectrometry and high-performance liquid chromatography to next-generation sequencing (NGS) and nanopore direct RNA sequencing, have enabled detailed studies of RNA modifications in cancer cells. Aberrant RNA modifications are associated with the dysregulation of tumor suppressor genes and oncogenes, influencing cancer progression, therapy resistance, and immune evasion. Emerging research suggests the therapeutic potential of targeting RNA-modifying enzymes and their inhibitors in cancer treatment. This review compiles and analyzes the latest findings on RNA modifications, presenting an in-depth discussion of the diverse chemical alterations that occur in RNA and their profound implications in cancer biology. It integrates fundamental principles with cutting-edge research, offering a holistic perspective on how RNA modifications influence gene expression, tumor progression, and therapeutic resistance. It emphasizes the need for further studies to elucidate the complex roles of RNA modifications in cancer, as well as the potential for multimodality therapeutic strategies that exploit the dynamic and reversible nature of these epitranscriptomic marks. It also attempts to highlight the challenges, gaps, and limitations of RNA modifications in cancer that should be tackled before their functional implications. Understanding the interplay between RNA modifications, cancer pathways, and their inhibitors will be crucial for developing promising RNA-based therapeutic approaches to cancer and personalized medicine strategies.
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Affiliation(s)
- Shalu Ranga
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana, 124001, India
| | - Ritu Yadav
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana, 124001, India.
| | - Meenakshi Chauhan
- Department of Obstetrics and Gynaecology, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, 124001, India
| | - Ravindresh Chhabra
- Department of Biochemistry, Central University of Panjab, Bathinda, Panjab, 151401, India
| | - Parul Ahuja
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana, 124001, India
| | - Nikita Balhara
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana, 124001, India
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Yang Y, Sakurai M. Advances in Detection Methods for A-to-I RNA Editing. WILEY INTERDISCIPLINARY REVIEWS. RNA 2025; 16:e70014. [PMID: 40223708 PMCID: PMC11995373 DOI: 10.1002/wrna.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/28/2025] [Accepted: 03/31/2025] [Indexed: 04/15/2025]
Abstract
Adenosine-to-inosine (A-to-I) RNA editing is a key post-transcriptional modification that influences gene expression and various cellular processes. Advances in sequencing technologies have greatly contributed to the identification of A-to-I editing sites, providing insights into their distribution across coding and non-coding regions. These developments have facilitated the discovery of functionally relevant editing events and have advanced the understanding of their biological roles. This review presents the evolution of methodologies for RNA editing detection and examines recent advances, including chemically-assisted, enzyme-assisted, and quantitative approaches. By evaluating these techniques, we aim to help researchers select the most effective tools for investigating RNA editing and its broader implications in health and disease.
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Affiliation(s)
- Yuxi Yang
- Research Institute for Biomedical SciencesTokyo University of ScienceChibaJapan
| | - Masayuki Sakurai
- Research Institute for Biomedical SciencesTokyo University of ScienceChibaJapan
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Deng Z, Jin X, Liu B, Zhen H, Wang X. Unveiling the prognostic significance of RNA editing-related genes in colon cancer: evidence from bioinformatics and experiment. Eur J Med Res 2025; 30:94. [PMID: 39940052 PMCID: PMC11823094 DOI: 10.1186/s40001-025-02335-7] [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: 10/19/2024] [Accepted: 01/26/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND RNA editing is recognized as a crucial factor in cancer biology. Its potential application in predicting the prognosis of colon adenocarcinoma (COAD) remains unexplored. METHODS RNA editing data of COAD patients were downloaded from the Synapse database. LASSO regression was used to construct the risk model and verified by the receiver operating characteristic (ROC) curve. GO and KEGG enrichment analyses were performed to delineate the biological significance of the differentially expressed genes. Finally, differential analysis and immunohistochemistry were used to verify the expression of adenosine deaminase 1 (ADAR1). RESULTS We evaluated a total of 4079 RNA editing sites in 514 COAD patients from Synapse database. A prognostic signature was constructed based on five genes were significantly associated with the prognosis of COAD patients including GNL3L, NUP43, MAGT1, EMP2, and ARSD. Univariate and multivariate Cox regression analysis revealed that RNA editing-related genes (RERGs)-related signature was an independent risk factor for COAD. Moreover, Experimental evidence shows that ADAR1 is highly expressed in colon adenocarcinoma and silencing ADAR1 can inhibit cancer cell proliferation. CONCLUSION We established a prognostic model based on five RERGs with strong predictive value. This model not only serves as a foundation for a novel prognostic tool but also facilitates the identification of potential drug candidates for treating COAD.
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Affiliation(s)
- Zhengcong Deng
- Hubei Third People's Hospital, Wuhan, 430033, Hubei, China
- Wuhan Donghu New Technology Development Zone Disease Prevention and Control Center, Wuhan, 430200, Hubei, China
| | - Xueqin Jin
- Hubei Third People's Hospital, Wuhan, 430033, Hubei, China
| | - Bingxue Liu
- Medical School, Jianghan University, Wuhan, 430056, Hubei, China
| | - Hongyan Zhen
- Medical School, Jianghan University, Wuhan, 430056, Hubei, China
| | - Xiang Wang
- Medical School, Jianghan University, Wuhan, 430056, Hubei, China.
- Wuhan University of Arts and Science, Wuhan, 430345, Hubei, China.
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Kim HS, Eun JW, Jang SH, Kim JY, Jeong JY. The diverse landscape of RNA modifications in cancer development and progression. Genes Genomics 2025; 47:135-155. [PMID: 39643826 DOI: 10.1007/s13258-024-01601-y] [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: 10/25/2024] [Accepted: 11/22/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND RNA modifications, a central aspect of epitranscriptomics, add a regulatory layer to gene expression by modifying RNA function without altering nucleotide sequences. These modifications play vital roles across RNA species, influencing RNA stability, translation, and interaction dynamics, and are regulated by specific enzymes that add, remove, and interpret these chemical marks. OBJECTIVE This review examines the role of aberrant RNA modifications in cancer progression, exploring their potential as diagnostic and prognostic biomarkers and as therapeutic targets. We focus on how altered RNA modification patterns impact oncogenes, tumor suppressor genes, and overall tumor behavior. METHODS We performed an in-depth analysis of recent studies and advances in RNA modification research, highlighting key types and functions of RNA modifications and their roles in cancer biology. Studies involving preclinical models targeting RNA-modifying enzymes were reviewed to assess therapeutic efficacy and potential clinical applications. RESULTS Aberrant RNA modifications were found to significantly influence cancer initiation, growth, and metastasis. Dysregulation of RNA-modifying enzymes led to altered gene expression profiles in oncogenes and tumor suppressors, correlating with tumor aggressiveness, patient outcomes, and response to immunotherapy. Notably, inhibitors of these enzymes demonstrated potential in preclinical models by reducing tumor growth and enhancing the efficacy of existing cancer treatments. CONCLUSIONS RNA modifications present promising avenues for cancer diagnosis, prognosis, and therapy. Understanding the mechanisms of RNA modification dysregulation is essential for developing targeted treatments that improve patient outcomes. Further research will deepen insights into these pathways and support the clinical translation of RNA modification-targeted therapies.
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Affiliation(s)
- Hyung Seok Kim
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea
| | - Jung Woo Eun
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, 16499, South Korea
| | - Se Ha Jang
- Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, 16499, South Korea
| | - Ji Yun Kim
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan, 49267, South Korea.
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Adamczak D, Fornalik M, Małkiewicz A, Pestka J, Pławski A, Jagodziński PP, Słowikowski BK. ADAR1 expression in different cancer cell lines and its change under heat shock. J Appl Genet 2024:10.1007/s13353-024-00926-4. [PMID: 39641903 DOI: 10.1007/s13353-024-00926-4] [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: 07/02/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 12/07/2024]
Abstract
Adenosine deaminase acting on RNA 1 (ADAR1) plays an essential role in the development of malignancies by modifying the expression of different oncogenes. ADAR1 presents three distinct activities: adenosine-to-inosine RNA editing, modulating IFN pathways, and response to cellular stress factors. Following stressors such as heat shock, ADAR1p110 isoform relocates from the nucleus to the cytoplasm, where it suppresses RNA degradation which leads to the arrest of apoptosis and cell survival. In this study, we assessed the expression of ADAR1 across different cancer cell lines. We revealed that the presence of ADAR1 varies between cells of different origins and that a high transcript level does not reflect protein abundance. Additionally, we subjected cells to a heat shock in order to evaluate how cellular stress factors affect the expression of ADAR1. Our results indicate that ADAR1 transcript and protein levels are relatively stable and do not change under heat shock in examined cell lines. This research lays a groundwork for future directions on ADAR1-related studies suggesting in which types of cancer ADAR1 may be a promising target for novel therapeutic approaches.
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Affiliation(s)
- Dominika Adamczak
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Michał Fornalik
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Anna Małkiewicz
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Julia Pestka
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Andrzej Pławski
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32 Street, 60-479, Poznań, Poland
| | - Paweł Piotr Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland
| | - Bartosz Kazimierz Słowikowski
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Święcickiego 6 Street, 60-781, Poznań, Poland.
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He D, Niu C, Bai R, Chen N, Cui J. ADAR1 Promotes Invasion and Migration and Inhibits Ferroptosis via the FAK/AKT Pathway in Colorectal Cancer. Mol Carcinog 2024; 63:2401-2413. [PMID: 39239920 DOI: 10.1002/mc.23818] [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: 05/06/2024] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 09/07/2024]
Abstract
The role of adenosine deaminase acting on RNA1 (ADAR1) in colorectal cancer (CRC) is poorly understood. This study investigated the roles and underlying molecular mechanisms of ADAR1 and its isoforms, explored the correlations between ADAR1 expression and the immune microenvironment and anticancer drug sensitivity, and examined the potential synergy of using ADAR1 expression and clinical parameters to determine the prognosis of CRC patients. CRC samples showed significant upregulation of ADAR1, and high ADAR1 expression was correlated with poor prognosis. Silencing ADAR1 inhibited the proliferation, invasion, and migration of CRC cells and induced ferroptosis by suppressing FAK/AKT activation, and the results of rescue assays were consistent with these mechanisms. Both ADAR1-p110 and ADAR1-p150 were demonstrated to regulate the FAK/AKT pathway, with ADAR1-p110 playing a particularly substantial role. In evaluating the prognosis of CRC patients, combining ADAR1 expression with clinical parameters produced a substantial synergistic effect. The in vivo tumorigenesis of CRC was significantly inhibited by silencing ADAR1. Furthermore, ADAR1 expression was positively correlated with tumor mutational burden (TMB) and microsatellite status (p < 0.05), indicating that ADAR1 plays a complex role in CRC immunotherapy. In conclusion, ADAR1 plays oncogenic roles in CRC both in vitro and in vivo, potentially by inhibiting ferroptosis via downregulation of the FAK/AKT pathway. Thus, ADAR1 serves as a potential prognostic biomarker and a promising target for CRC therapy.
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Affiliation(s)
- Dongsheng He
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Chao Niu
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Rilan Bai
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Naifei Chen
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Jiuwei Cui
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China
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Liu Q, Huang C, Chen S, Zhu Y, Huang X, Zhao G, Xu Q, Shi Y, Li W, Wang R, Yin X. ADAR1 promotes cisplatin resistance in intrahepatic cholangiocarcinoma by regulating BRCA2 expression through A-to-I editing manner. Cell Prolif 2024; 57:e13659. [PMID: 38773866 PMCID: PMC11471395 DOI: 10.1111/cpr.13659] [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: 03/22/2024] [Revised: 04/20/2024] [Accepted: 05/03/2024] [Indexed: 05/24/2024] Open
Abstract
Aberrant A-to-I RNA editing, mediated by ADAR1 has been found to be associated with increased tumourigenesis and the development of chemotherapy resistance in various types of cancer. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis, and overcoming chemotherapy resistance poses a significant clinical challenge. This study aimed to clarify the roles of ADAR1 in tumour resistance to cisplatin in iCCA. We discovered that ADAR1 expression is elevated in iCCA patients, particularly in those resistant to cisplatin, and associated with poor clinical outcomes. Downregulation of ADAR1 can increase the sensitivity of iCCA cells to cisplatin treatment, whereas its overexpression has the inverse effect. By integrating RNA sequencing and Sanger sequencing, we identified BRCA2, a critical DNA damage repair gene, as a downstream target of ADAR1 in iCCA. ADAR1 mediates the A-to-I editing in BRCA2 3'UTR, inhibiting miR-3157-5p binding, consequently increasing BRCA2 mRNA and protein levels. Furthermore, ADAR1 enhances cellular DNA damage repair ability and facilitates cisplatin resistance in iCCA cells. Combining ADAR1 targeting with cisplatin treatment markedly enhances the anticancer efficacy of cisplatin. In conclusion, ADAR1 promotes tumour progression and cisplatin resistance of iCCA. ADAR1 targeting could inform the development of innovative combination therapies for iCCA.
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Affiliation(s)
- Qi Liu
- Department of Pancreato‐Biliary SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Chen‐Song Huang
- Department of Pancreato‐Biliary SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Siyun Chen
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat‐sen University)Ministry of EducationGuangzhouChina
| | - Ying‐Qin Zhu
- Department of Pancreato‐Biliary SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Xi‐Tai Huang
- Department of Pancreato‐Biliary SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Guang‐Yin Zhao
- Department of Animal Experiment Center, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Qiong‐Cong Xu
- Department of Pancreato‐Biliary SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yin‐Hao Shi
- Department of Pancreato‐Biliary SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Wen Li
- Laboratory of General Surgery, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Ruizhi Wang
- Department of Laboratory Medicine, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Xiao‐Yu Yin
- Department of Pancreato‐Biliary SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
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Nian Z, Deng M, Ye L, Tong X, Xu Y, Xu Y, Chen R, Wang Y, Mao F, Xu C, Lu R, Mao Y, Xu H, Shen X, Xue X, Guo G. RNA epigenetic modifications in digestive tract cancers: Friends or foes. Pharmacol Res 2024; 206:107280. [PMID: 38914382 DOI: 10.1016/j.phrs.2024.107280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Digestive tract cancers are among the most common malignancies worldwide and have high incidence and mortality rates. Thus, the discovery of more effective diagnostic and therapeutic targets is urgently required. The development of technologies to accurately detect RNA modification has led to the identification of numerous RNA chemical modifications in humans (epitranscriptomics) that are involved in the occurrence and development of digestive tract cancers. RNA modifications can cooperatively regulate gene expression to facilitate normal physiological functions of the digestive system. However, the dysfunction of relevant RNA-modifying enzymes ("writers," "erasers," and "readers") can lead to the development of digestive tract cancers. Consequently, targeting dysregulated enzyme activity could represent a potent therapeutic strategy for the treatment of digestive tract cancers. In this review, we summarize the most widely studied roles and mechanisms of RNA modifications (m6A, m1A, m5C, m7G, A-to-I editing, pseudouridine [Ψ]) in relation to digestive tract cancers, highlight the crosstalk between RNA modifications, and discuss their roles in the interactions between the digestive system and microbiota during carcinogenesis. The clinical significance of novel therapeutic methods based on RNA-modifying enzymes is also discussed. This review will help guide future research into digestive tract cancers that are resistant to current therapeutics.
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Affiliation(s)
- Zekai Nian
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Ming Deng
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Lele Ye
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xinya Tong
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yixi Xu
- School of public administration, Hangzhou Normal University, Hangzhou, China
| | - Yiliu Xu
- Research Center of Fluid Machinery Engineering & Technology, Jiangsu University, Zhenjiang, China
| | - Ruoyao Chen
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Yulin Wang
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Feiyang Mao
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Chenyv Xu
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ruonan Lu
- First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Yicheng Mao
- Ophthalmology College, Wenzhou Medical University, Wenzhou, China
| | - Hanlu Xu
- Ophthalmology College, Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xiangyang Xue
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
| | - Gangqiang Guo
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
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Chen C, Bundschuh R. A-to-I Editing Is Subtype-Specific in Non-Hodgkin Lymphomas. Genes (Basel) 2024; 15:864. [PMID: 39062643 PMCID: PMC11276283 DOI: 10.3390/genes15070864] [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: 05/17/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Cancer is a complex and heterogeneous disease, in which a number of genetic and epigenetic changes occur in tumor onset and progression. Recent studies indicate that changes at the RNA level are also involved in tumorigenesis, such as adenosine-to-inosine (A-to-I) RNA editing. Here, we systematically investigate transcriptome-wide A-to-I editing events in a large number of samples from Non-Hodgkin lymphomas (NHLs). Using a computational pipeline that determines significant differences in editing level between NHL and normal samples at known A-to-I editing sites, we identify a number of differentially edited editing sites between NHL subtypes and normal samples. Most of the differentially edited sites are located in non-coding regions, and many such sites show a strong correlation between gene expression level and editing efficiency, indicating that RNA editing might have direct consequences for the cancer cell's aberrant gene regulation status in these cases. Moreover, we establish a strong link between RNA editing and NHL by demonstrating that NHL and normal samples and even NHL subtypes can be distinguished based on genome-wide RNA editing profiles alone. Our study establishes a strong link between RNA editing, cancer and aberrant gene regulation in NHL.
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Affiliation(s)
- Cai Chen
- Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA
- Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA
| | - Ralf Bundschuh
- Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA
- Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA
- Department of Physics, The Ohio State University, Columbus, OH 43210, USA
- Department of Chemistry & Biochemistry, The Ohio State University, Columbus, OH 43210, USA
- Division of Hematology, The Ohio State University, Columbus, OH 43210, USA
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12
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Zhu T, Li Q, Zhang Z, Shi J, Li Y, Zhang F, Li L, Song X, Shen J, Jia R. ARID1A loss promotes RNA editing of CDK13 in an ADAR1-dependent manner. BMC Biol 2024; 22:132. [PMID: 38835016 PMCID: PMC11151582 DOI: 10.1186/s12915-024-01927-9] [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: 07/11/2023] [Accepted: 05/22/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is thought to play a significant role both in tumor suppression and tumor initiation, which is highly dependent upon context. Previous studies have suggested that ARID1A deficiency may contribute to cancer development. The specific mechanisms of whether ARID1A loss affects tumorigenesis by RNA editing remain unclear. RESULTS Our findings indicate that the deficiency of ARID1A leads to an increase in RNA editing levels and alterations in RNA editing categories mediated by adenosine deaminases acting on RNA 1 (ADAR1). ADAR1 edits the CDK13 gene at two previously unidentified sites, namely Q113R and K117R. Given the crucial role of CDK13 as a cyclin-dependent kinase, we further observed that ADAR1 deficiency results in changes in the cell cycle. Importantly, the sensitivity of ARID1A-deficient tumor cells to SR-4835, a CDK12/CDK13 inhibitor, suggests a promising therapeutic approach for individuals with ARID1A-mutant tumors. Knockdown of ADAR1 restored the sensitivity of ARID1A deficient cells to SR-4835 treatment. CONCLUSIONS ARID1A deficiency promotes RNA editing of CDK13 by regulating ADAR1.
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Affiliation(s)
- Tianyu Zhu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Qian Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Zhe Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Jiahao Shi
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Yongyun Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China
| | - Feng Zhang
- Department of Histoembryology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Lingjie Li
- Department of Histoembryology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Xin Song
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China.
| | - Jianfeng Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China.
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China.
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13
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Zhu Z, Lu J. Development and assessment of an RNA editing-based risk model for the prognosis of cervical cancer patients. Medicine (Baltimore) 2024; 103:e38116. [PMID: 38728474 PMCID: PMC11081546 DOI: 10.1097/md.0000000000038116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/12/2024] [Indexed: 05/12/2024] Open
Abstract
RNA editing, as an epigenetic mechanism, exhibits a strong correlation with the occurrence and development of cancers. Nevertheless, few studies have been conducted to investigate the impact of RNA editing on cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). In order to study the connection between RNA editing and CESC patients' prognoses, we obtained CESC-related information from The Cancer Genome Atlas (TCGA) database and randomly allocated the patients into the training group or testing group. An RNA editing-based risk model for CESC patients was established by Cox regression analysis and least absolute shrinkage and selection operator (LASSO). According to the median score generated by this RNA editing-based risk model, patients were categorized into subgroups with high and low risks. We further constructed the nomogram by risk scores and clinical characteristics and analyzed the impact of RNA editing levels on host gene expression levels and adenosine deaminase acting on RNA. Finally, we also compared the biological functions and pathways of differentially expressed genes (DEGs) between different subgroups by enrichment analysis. In this risk model, we screened out 6 RNA editing sites with significant prognostic value. The constructed nomogram performed well in forecasting patients' prognoses. Furthermore, the level of RNA editing at the prognostic site exhibited a strong correlation with host gene expression. In the high-risk subgroup, we observed multiple biological functions and pathways associated with immune response, cell proliferation, and tumor progression. This study establishes an RNA editing-based risk model that helps forecast patients' prognoses and offers a new understanding of the underlying mechanism of RNA editing in CESC.
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Affiliation(s)
- Zihan Zhu
- Department of Biostatistics, School of Public Health, Nanjing Medical University 101 Longmian Avenue, Nanjing, P.R. China
| | - Jing Lu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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14
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Lu Q, Zhou W, Fan L, Ding T, Wang W, Zhang X. Tumor neoantigens derived from RNA editing events show significant clinical relevance in melanoma patients treated with immunotherapy. Anticancer Drugs 2024; 35:305-314. [PMID: 38170793 DOI: 10.1097/cad.0000000000001565] [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: 01/05/2024]
Abstract
This study aimed to investigate the clinical significance of RNA editing (RE) and RNA editing derived (RED-) neoantigens in melanoma patients treated with immunotherapy. Vardict and VEP were used to identify the somatic mutations. RE events were identified by Reditools2 and filtered by the custom pipeline. miRTar2GO was implemented to predict the RE whether located in miRNA targets within the 3' UTR region. NetMHCpan and NetCTLpan were used to identify and characterize RED-neoantigens. In total, 7116 RE events were identified, most of which were A-to-I events. Using our custom pipeline, 631 RED-neoantigens were identified that show a significantly greater peptide-MHC affinity, and facilitate epitope processing and presentation than wild-type peptides. The OS of the patients with high RED-neoantigens burden was significantly longer ( P = 0.035), and a significantly higher RED-neoantigens burden was observed in responders ( P = 0.048). The area under the curve of the RED-neoantigen was 0.831 of OS. Then, we validated the reliability of RED-neoantigens in predicting the prognosis in an independent cohort and found that patients with high RED-neoantigens exhibited a longer OS ( P = 0.008). To our knowledge, this is the first study to systematically assess the clinical relevance of RED-neoantigens in melanoma patients treated with immunotherapy.
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Affiliation(s)
- Qicheng Lu
- Department of Gastrointestinal Surgery, Changzhou First People's Hospital, Changzhou, Jiangsu
| | - Wenhao Zhou
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd., Shenzhen, Guangdong
| | - Ligang Fan
- Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou
| | - Tian Ding
- Department of Clinical Medicine, Medical School, Nantong University
| | - Wei Wang
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd., Shenzhen, Guangdong
| | - Xiaodong Zhang
- Department of Medical Oncology, Tumor Hospital Affiliated To Nantong University, Nantong, Jiangsu, China
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15
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Qian CJ, He YS, Guo T, Tao J, Wei ZY, Zhang JL, Bao C, Chen JH. ADAR-mediated RNA editing regulates PVR immune checkpoint in colorectal cancer. Biochem Biophys Res Commun 2024; 695:149373. [PMID: 38176170 DOI: 10.1016/j.bbrc.2023.149373] [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: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 01/06/2024]
Abstract
Recent studies have revealed that tumor immunotherapy resistance is influenced by ADAR-mediated RNA editing, but its targets remain unelucidated. Our current study identified the poliovirus receptor (PVR) oncogene, which encodes an immune checkpoint in colorectal cancer (CRC), as a potential target for RNA editing. We performed transcriptome sequencing analysis and experimental validation in two Chinese CRC cohorts. PVR and ADAR expressions significantly increased in CRC tumors and showed positive correlations in both cohorts, coupled with upregulated PVR RNA editing in CRC tumors. Manipulation of ADAR expression by over-expression or knockdown substantially changed PVR expression and RNA editing in HTC116 CRC cells. Luciferase reporter and actinomycin D assays further revealed that RNA editing in PVR 3'-UTR could upregulate PVR RNA expression, probably by increasing the RNA stability. By increasing PVR expression, ADAR-mediate RNA editing might contribute to tumor- and immune-related gene functions and pathways in CRC. Moreover, a signature combining PVR RNA editing and expression showed promising predictive performance in CRC diagnosis in both Chinese CRC cohorts. Our findings thus highlight the importance of ADAR-mediated RNA editing in PVR up-regulation in CRC tumors and provide new insight into the application of PVR RNA editing as a novel diagnostic biomarker for CRC.
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Affiliation(s)
- Cheng-Jia Qian
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, China
| | - Yu-Shan He
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, China; Joint Primate Research Center for Chronic Diseases, Jiangnan University and Institute of Zoology, Guangdong Academy of Science, Guangzhou, China; Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Tao Guo
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, China; Joint Primate Research Center for Chronic Diseases, Jiangnan University and Institute of Zoology, Guangdong Academy of Science, Guangzhou, China; Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Ji Tao
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, China; Joint Primate Research Center for Chronic Diseases, Jiangnan University and Institute of Zoology, Guangdong Academy of Science, Guangzhou, China; Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Zhi-Yuan Wei
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, China; Joint Primate Research Center for Chronic Diseases, Jiangnan University and Institute of Zoology, Guangdong Academy of Science, Guangzhou, China; Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Jia-Li Zhang
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, China; Joint Primate Research Center for Chronic Diseases, Jiangnan University and Institute of Zoology, Guangdong Academy of Science, Guangzhou, China; Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Chuanqing Bao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, No. 1000 Hefeng Road, Wuxi, China.
| | - Jian-Huan Chen
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, China; Joint Primate Research Center for Chronic Diseases, Jiangnan University and Institute of Zoology, Guangdong Academy of Science, Guangzhou, China; Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China.
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16
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Zheng J, Lu Y, Lin Y, Si S, Guo B, Zhao X, Cui L. Epitranscriptomic modifications in mesenchymal stem cell differentiation: advances, mechanistic insights, and beyond. Cell Death Differ 2024; 31:9-27. [PMID: 37985811 PMCID: PMC10782030 DOI: 10.1038/s41418-023-01238-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/24/2023] [Accepted: 11/06/2023] [Indexed: 11/22/2023] Open
Abstract
RNA modifications, known as the "epitranscriptome", represent a key layer of regulation that influences a wide array of biological processes in mesenchymal stem cells (MSCs). These modifications, catalyzed by specific enzymes, often termed "writers", "readers", and "erasers", can dynamically alter the MSCs' transcriptomic landscape, thereby modulating cell differentiation, proliferation, and responses to environmental cues. These enzymes include members of the classes METTL, IGF2BP, WTAP, YTHD, FTO, NAT, and others. Many of these RNA-modifying agents are active during MSC lineage differentiation. This review provides a comprehensive overview of the current understanding of different RNA modifications in MSCs, their roles in regulating stem cell behavior, and their implications in MSC-based therapies. It delves into how RNA modifications impact MSC biology, the functional significance of individual modifications, and the complex interplay among these modifications. We further discuss how these intricate regulatory mechanisms contribute to the functional diversity of MSCs, and how they might be harnessed for therapeutic applications. The review also highlights current challenges and potential future directions in the study of RNA modifications in MSCs, emphasizing the need for innovative tools to precisely map these modifications and decipher their context-specific effects. Collectively, this work paves the way for a deeper understanding of the role of the epitranscriptome in MSC biology, potentially advancing therapeutic strategies in regenerative medicine and MSC-based therapies.
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Affiliation(s)
- Jiarong Zheng
- Department of Dentistry, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Ye Lu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Yunfan Lin
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Shanshan Si
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Bing Guo
- Department of Dentistry, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Xinyuan Zhao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China.
| | - Li Cui
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China.
- Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, 90095, CA, USA.
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17
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GWAK SEUNGHEE, LEE JUHYUN, OH EUNJI, LEE DOHYUN, HAN WONSHIK, KIM JONGMIN, KIM KYONGTAI. Vaccinia-related kinase 2 variants differentially affect breast cancer growth by regulating kinase activity. Oncol Res 2023; 32:421-432. [PMID: 38186576 PMCID: PMC10765118 DOI: 10.32604/or.2023.031031] [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: 05/11/2023] [Accepted: 08/03/2023] [Indexed: 01/09/2024] Open
Abstract
Genetic information is transcribed from genomic DNA to mRNA, which is then translated into three-dimensional proteins. mRNAs can undergo various post-transcriptional modifications, including RNA editing that alters mRNA sequences, ultimately affecting protein function. In this study, RNA editing was identified at the 499th base (c.499) of human vaccinia-related kinase 2 (VRK2). This RNA editing changes the amino acid in the catalytic domain of VRK2 from isoleucine (with adenine base) to valine (with guanine base). Isoleucine-containing VRK2 has higher kinase activity than the valine-containing VRK2, which leads to an increase in tumor cell proliferation. Earlier we reported that VRK2 directly interacts with dystrobrevin-binding protein (dysbindin) and results in reducing its stability. Herein, we demonstrate that isoleucine-containing VRK2 decreases the level of dysbindin than valine-containing VRK2. Dysbindin interacts with cyclin D and thereby regulates its expression and function. The reduction in the level of dysbindin by isoleucine-containing VRK2 further enhances the cyclin D expression, resulting in increased tumor growth and reduction in survival rates. It has also been observed that in patient samples, VRK2 level was elevated in breast cancer tissue compared to normal breast tissue. Additionally, the isoleucine form of VRK2 exhibited a greater increase in breast cancer tissue. Therefore, it is concluded that VRK2, especially dependent on the 167th variant amino acid, can be one of the indexes of tumor progression and proliferation.
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Affiliation(s)
- SEUNG-HEE GWAK
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
| | - JUHYUN LEE
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
| | - EUNJI OH
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
| | - DOHYUN LEE
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
- R&D Center, NovMetaPharma Co., Ltd., Pohang, 37668, Korea
| | - WONSHIK HAN
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - JONGMIN KIM
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Korea
| | - KYONG-TAI KIM
- Generative Genomics Research Center, Global Green Research & Development Center, Handong Global University, Pohang, 37554, Korea
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18
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Kudrin P, Rebane A. Do RNA modifications contribute to modulation of immune responses in allergic diseases? FRONTIERS IN ALLERGY 2023; 4:1277244. [PMID: 38026133 PMCID: PMC10679440 DOI: 10.3389/falgy.2023.1277244] [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: 08/14/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
RNA modifications have emerged as a fundamental mechanism of post-transcriptional gene regulation, playing vital roles in cellular physiology and the development of various diseases. While the investigation of RNA modifications has seen significant advancements, the exploration of their implication in allergic diseases has been comparatively overlooked. Allergic reactions, including hay fever, asthma, eczema and food allergies, result from hypersensitive immune responses, affecting a considerable population worldwide. Despite the high prevalence, the molecular mechanisms underlying these responses remain partially understood. The potential role of RNA modifications in modulating the hypersensitive immune responses has yet to be fully elucidated. This mini-review seeks to shed light on potential connections between RNA modifications and allergy, highlighting recent findings and potential future research directions. By expanding our understanding of the complex interplay between RNA modifications and allergic responses, we hope to unlock new avenues for allergy diagnosis, prognosis, and therapeutic intervention.
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Affiliation(s)
- Pavel Kudrin
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
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19
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Frezza V, Chellini L, Del Verme A, Paronetto MP. RNA Editing in Cancer Progression. Cancers (Basel) 2023; 15:5277. [PMID: 37958449 PMCID: PMC10648226 DOI: 10.3390/cancers15215277] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/31/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
Coding and noncoding RNA molecules play their roles in ensuring cell function and tissue homeostasis in an ordered and systematic fashion. RNA chemical modifications can occur both at bases and ribose sugar, and, similarly to DNA and histone modifications, can be written, erased, and recognized by the corresponding enzymes, thus modulating RNA activities and fine-tuning gene expression programs. RNA editing is one of the most prevalent and abundant forms of post-transcriptional RNA modification in normal physiological processes. By altering the sequences of mRNAs, it makes them different from the corresponding genomic template. Hence, edited mRNAs can produce protein isoforms that are functionally different from the corresponding genome-encoded variants. Abnormalities in regulatory enzymes and changes in RNA-modification patterns are closely associated with the occurrence and development of various human diseases, including cancer. To date, the roles played by RNA modifications in cancer are gathering increasing interest. In this review, we focus on the role of RNA editing in cancer transformation and provide a new perspective on its impact on tumorigenesis, by regulating cell proliferation, differentiation, invasion, migration, stemness, metabolism, and drug resistance.
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Affiliation(s)
- Valentina Frezza
- Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, CERC, Via del Fosso di Fiorano, 64, 00143 Rome, Italy; (V.F.); (L.C.); (A.D.V.)
| | - Lidia Chellini
- Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, CERC, Via del Fosso di Fiorano, 64, 00143 Rome, Italy; (V.F.); (L.C.); (A.D.V.)
| | - Arianna Del Verme
- Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, CERC, Via del Fosso di Fiorano, 64, 00143 Rome, Italy; (V.F.); (L.C.); (A.D.V.)
| | - Maria Paola Paronetto
- Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, CERC, Via del Fosso di Fiorano, 64, 00143 Rome, Italy; (V.F.); (L.C.); (A.D.V.)
- Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
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20
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Tang Q, Li L, Wang Y, Wu P, Hou X, Ouyang J, Fan C, Li Z, Wang F, Guo C, Zhou M, Liao Q, Wang H, Xiang B, Jiang W, Li G, Zeng Z, Xiong W. RNA modifications in cancer. Br J Cancer 2023; 129:204-221. [PMID: 37095185 PMCID: PMC10338518 DOI: 10.1038/s41416-023-02275-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 03/30/2023] [Accepted: 04/06/2023] [Indexed: 04/26/2023] Open
Abstract
Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on m6A RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides m6A RNA methylation. In this review, we focus on several important RNA modifications including m1A, m5C, m7G, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.
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Affiliation(s)
- Qiling Tang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Lvyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Yumin Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Pan Wu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Xiangchan Hou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Jiawei Ouyang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Chunmei Fan
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Zheng Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Fuyan Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Can Guo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Ming Zhou
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
| | - Hui Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Weihong Jiang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China.
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21
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Shi S, Chen S, Wang M, Guo B, He Y, Chen H. Clinical relevance of RNA editing profiles in lung adenocarcinoma. Front Genet 2023; 14:1084869. [PMID: 36999050 PMCID: PMC10043753 DOI: 10.3389/fgene.2023.1084869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Background: Lung adenocarcinoma (LUAD) is the most frequently occurring lung cancer worldwide, with increasing death rates. It belongs to the non-small cell lung cancer (NSCLC) type and has a strong association with previous smoking history. Growing evidence has demonstrated the significance of adenosine-to-inosine RNA editing (ATIRE) dysregulation in cancer. The aim of the present study was to evaluate ATIRE events that might be clinically useful or tumorigenic.Methods: To explore survival-related ATIRE events in LUAD, its ATIRE profiles, gene expression data, and corresponding patients’ clinical information were downloaded from the Cancer Genome Atlas (TCGA) and the synapse database. We evaluated 10441 ATIRE in 440 LUAD patients from the TCGA database. ATIRE profiles were merged with TCGA survival data. We selected prognostic ATIRE sites, using a univariate Cox analysis (p < 0.001). Cox proportional hazards regression and lasso regression analysis were used to determine survival-related ATIRE sites, create risk ratings for those sites, and build a prognostic model and a nomogram for assessing overall survival (OS). Six ATIRE sites were used in the prognostic model construction and patients were randomly divided into a validation cohort (n = 176) and a training cohort (n = 264). The “Pheatmap” program was used to create risk curves that included risk score, survival time, and expression of ATIRE sites. We also determined the clinical prediction model’s discrimination. The decision curve analysis and the 1-, 2-, and 3-year corrective curves were simultaneously used to evaluate the nomogram. We also evaluated the relationship between the amount of ATIRE sites and host gene expression and the impact of ATIRE expression on transcriptome expression.Results: The pyroglutamyl-peptidase I (PGPEP1) chr19:18476416A > I, ankyrin repeat domain 36B pseudogene 1 (ANKRD36BP1) (dist = 3,795), T-box transcription factor (TBX19) (dist = 29815) chr1:168220463A > I, Syntrophin Beta 2 (SNTB2) chr16:69338598A > I, hook microtubule-tethering protein 3 (HOOK3) chr8:42883441A > I, NADH dehydrogenase flavoprotein 3 (NDUFV3) chr21:44329452A > I, and FK506-binding protein 11 (FKBP11) chr12:49316769A > I were used in the prognostic model construction. High levels of risk score were significantly associated with worse OS and progression-free survival. Tumour stage and risk score were related to OS in LUAD patients. The predictors were among the prognostic nomogram model’s risk score, age, gender, and tumor stage. The calibration plot and C-index (0.718) demonstrated the significant accuracy of nomogram’s predictions. ATIRE level was markedly elevated in tumor tissues and was highly variable between patients.Conclusion: Events involving ATIRE in LUAD were highly functional and clinically relevant. The RNA editing-based model provides a solid framework for further investigation of the functions of RNA editing in non-coding areas and may be used as a unique method for predicting LUAD survival.
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Affiliation(s)
- Si Shi
- The Respiratory Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shibin Chen
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Menghang Wang
- The Respiratory Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Bingchen Guo
- Department of Cardiology, The first Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yaowu He
- The Respiratory Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hong Chen
- The Respiratory Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- *Correspondence: Hong Chen,
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22
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Guo M, Li F, Zhao L, Fang Z, Yu H, Songyang Z, Xiong Y. Pan-cancer investigation of C-to-U editing reveals its important role in cancer development and new targets for cancer treatment. Front Oncol 2023; 13:1097667. [PMID: 36969056 PMCID: PMC10034049 DOI: 10.3389/fonc.2023.1097667] [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: 11/17/2022] [Accepted: 02/20/2023] [Indexed: 03/11/2023] Open
Abstract
RNA editing is prevalent in the transcriptome and is important for multiple cellular processes. C-to-U RNA editing sites (RES) are relatively rare and understudied in humans, compared to A-to-I editing. However, the functional impact of C-to-U editing in human cancers also remains elusive. Here, we conducted the first comprehensive survey of pan-cancer C-to-U RESs. Surprisingly, we found that the same subset of RESs were associated with multiple features, including patient survival, cancer stemness, tumor mutation burden (TMB), and tumor-infiltrated immune cell compositions (ICC), suggesting an RES-mediated close relationship between these features. For example, editing sites for GALM or IFI6 that led to higher expression were linked to lower survival and more cancer stemness. Also, TMB was found to be lower in prostate cancer cases with ICC-associated RESs in CAVIN1 or VWA8 or higher in prostate cancer cases with thymoma. With experimental support, we also found RESs in CST3, TPI1, or TNC that are linked to immune checkpoint blockade by anti-PD1. We also confirmed through experiments that two C-to-U RESs in CSNK2B or RPS14 had different effects on colon cancer cells. Patients with CSNK2B editing, which increased the expression of the oncogene CLDN18, had a lower response to drugs. On the other hand, drugs worked better on people who had RPS14 editing, which greatly increased ribosome production. In summary, our study demonstrated the important roles of C-to-U RESs across cancers and shed light on personalized cancer therapy.
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Affiliation(s)
- Mengbiao Guo
- Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Feng Li
- Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Linghao Zhao
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhengwen Fang
- Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Huichuan Yu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhou Songyang
- Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yuanyan Xiong
- Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
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23
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Niu L, Liu L, Cai J. A novel strategy for precise prognosis management and treatment option in colon adenocarcinoma with TP53 mutations. Front Surg 2023; 10:1079129. [PMID: 36843983 PMCID: PMC9947352 DOI: 10.3389/fsurg.2023.1079129] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 01/10/2023] [Indexed: 02/11/2023] Open
Abstract
Background TP53 is one of the most frequent mutated genes in colon cancer. Although colon cancer with TP53 mutations has a high risk of metastasis and worse prognosis generally, it showed high heterogeneity clinically. Methods A total of 1,412 colon adenocarcinoma (COAD) samples were obtained from two RNA-seq cohorts and three microarray cohorts, including the TCGA-COAD (N = 408), the CPTAC-COAD (N = 106), GSE39582 (N = 541), GSE17536 (N = 171) and GSE41258 (N = 186). The LASSO-Cox method was used to establish the prognostic signature based on the expression data. The patients were divided into high-risk and low-risk groups based on the median risk score. The efficiency of the prognostic signature was validated in various cohorts, including TP53-mutant and TP53 wild-type. The exploration of potential therapeutic targets and agents was performed by using the expression data of TP53-mutant COAD cell lines obtained from the CCLE database and the corresponding drug sensitivity data obtained from the GDSC database. Results A 16-gene prognostic signature was established in TP53-mutant COAD. The high-risk group had significantly inferior survival time compared to the low-risk group in all TP53-mutant datasets, while the prognostic signature failed to classify the prognosis of COAD with TP53 wild-type properly. Besides, the risk score was the independent poor factor for the prognosis in TP53-mutant COAD and the nomogram based on the risk score was also shown good predictive efficiency in TP53-mutant COAD. Moreover, we identified SGPP1, RHOQ, and PDGFRB as potential targets for TP53-mutant COAD, and illuminated that the high-risk patients might benefit from IGFR-3801, Staurosporine, and Sabutoclax. Conclusion A novel prognostic signature with great efficiency was established especially for COAD patients with TP53 mutations. Besides, we identified novel therapeutic targets and potential sensitive agents for TP53-mutant COAD with high risk. Our findings provided not only a new strategy for prognosis management but also new clues for drug application and precision treatment in COAD with TP53 mutations.
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24
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Wang SY, Zhang LJ, Chen GJ, Ni QQ, Huang Y, Zhang D, Han FY, He WF, He LL, Ding YQ, Jiao HL, Ye YP. COPA A-to-I RNA editing hijacks endoplasmic reticulum stress to promote metastasis in colorectal cancer. Cancer Lett 2023; 553:215995. [PMID: 36336148 DOI: 10.1016/j.canlet.2022.215995] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
Abstract
RNA editing is among the most common RNA level modifications for generating amino acid changes. We identified a COPA A-to-I RNA editing event in CRC metastasis. Our results showed that the COPA A-to-I RNA editing rate was significantly increased in metastatic CRC tissues and was closely associated with aggressive tumors in the T and N stages. The COPA I164V protein damaged the Golgi-ER reverse transport function, induced ER stress, promoted the translocation of the transcription factors ATF6, XBP1 and ATF4 into the nucleus, and activated the expression of MALAT1, MET, ZEB1, and lead to CRC cell invasion and metastasis. Moreover, the COPA A-to-I RNA editing rate was positively correlated with the immune infiltration score. Collectively, the COPA I164V protein hijacked ER stress to promote the metastasis of CRC, and the COPA A-to-I RNA editing rate may be a potential predictor for patient response to immune checkpoint inhibitor (ICIs) treatment.
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Affiliation(s)
- Shu-Yang Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Ling-Jie Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Guo-Jun Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Qi-Qi Ni
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Yuan Huang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Dan Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Fang-Yi Han
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Wen-Feng He
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Li-Ling He
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Yan-Qing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China.
| | - Hong-Li Jiao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China.
| | - Ya-Ping Ye
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China.
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25
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Zhang Z, Chen P, Yun J. Comprehensive analysis of a novel RNA modifications-related model in the prognostic characterization, immune landscape and drug therapy of bladder cancer. Front Genet 2023; 14:1156095. [PMID: 37124622 PMCID: PMC10131083 DOI: 10.3389/fgene.2023.1156095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/31/2023] [Indexed: 05/02/2023] Open
Abstract
Background: Bladder cancer (BCa) is the leading reason for death among genitourinary malignancies. RNA modifications in tumors closely link to the immune microenvironment. Our study aimed to propose a promising model associated with the "writer" enzymes of five primary RNA adenosine modifications (including m6A, m6Am, m1A, APA, and A-to-I editing), thus characterizing the clinical outcome, immune landscape and therapeutic efficacy of BCa. Methods: Unsupervised clustering was employed to categorize BCa into different RNA modification patterns based on gene expression profiles of 34 RNA modification "writers". The RNA modification "writers" score (RMS) signature composed of RNA phenotype-associated differentially expressed genes (DEGs) was established using the least absolute shrinkage and selection operator (LASSO), which was evaluated in meta-GEO (including eight independent GEO datasets) training cohort and the TCGA-BLCA validation cohort. The hub genes in the RMS model were determined via weighted gene co-expression network analysis (WGCNA) and were further validated using human specimen. The potential applicability of the RMS model in predicting the therapeutic responsiveness was assessed through the Genomics of Drug Sensitivity in Cancer database and multiple immunotherapy datasets. Results: Two distinct RNA modification patterns were determined among 1,410 BCa samples from a meta-GEO cohort, showing radically varying clinical outcomes and biological characteristics. The RMS model comprising 14 RNA modification phenotype-associated prognostic DEGs positively correlated with the unsatisfactory outcome of BCa patients in meta-GEO training cohort (HR = 3.00, 95% CI = 2.19-4.12) and TCGA-BLCA validation cohort (HR = 1.53, 95% CI = 1.13-2.09). The infiltration of immunosuppressive cells and the activation of EMT, angiogenesis, IL-6/JAK/STAT3 signaling were markedly enriched in RMS-high group. A nomogram exhibited high prognostic prediction accuracy, with a concordance index of 0.785. The therapeutic effect of chemotherapeutic agents and antibody-drug conjugates was significantly different between RMS-low and -high groups. The combination of the RMS model and conventional characteristics (TMB, TNB and PD-L1) achieved an optimal AUC value of 0.828 in differentiating responders from non-responders to immunotherapy. Conclusion: We conferred the first landscape of five forms of RNA modifications in BCa and emphasized the excellent power of an RNA modifications-related model in evaluating BCa prognosis and immune landscape.
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Affiliation(s)
- Ziying Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Peng Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jingping Yun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- *Correspondence: Jingping Yun,
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26
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Gan WL, Ng L, Ng BYL, Chen L. Recent Advances in Adenosine-to-Inosine RNA Editing in Cancer. Cancer Treat Res 2023; 190:143-179. [PMID: 38113001 DOI: 10.1007/978-3-031-45654-1_5] [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: 12/21/2023]
Abstract
RNA epigenetics, or epitranscriptome, is a growing group of RNA modifications historically classified into two categories: RNA editing and RNA modification. RNA editing is usually understood as post-transcriptional RNA processing (except capping, splicing and polyadenylation) that changes the RNA nucleotide sequence encoded by the genome. This processing can be achieved through the insertion or deletion of nucleotides or deamination of nucleobases, generating either standard nucleotides such as uridine (U) or the rare nucleotide inosine (I). Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent type of RNA modification in mammals and is catalyzed by adenosine deaminase acting on the RNA (ADAR) family of enzymes that recognize double-stranded RNAs (dsRNAs). Inosine mimics guanosine (G) in base pairing with cytidine (C), thereby A-to-I RNA editing alters dsRNA secondary structure. Inosine is also recognized as guanosine by the splicing and translation machineries, resulting in mRNA alternative splicing and protein recoding. Therefore, A-to-I RNA editing is an important mechanism that causes and regulates "RNA mutations" in both normal physiology and diseases including cancer. In this chapter, we reviewed current paradigms and developments in the field of A-to-I RNA editing in the context of cancer.
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Affiliation(s)
- Wei Liang Gan
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore
| | - Larry Ng
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore
| | - Bryan Y L Ng
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore
| | - Leilei Chen
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
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Gao C, Zhou G, Shi J, Shi P, Jin L, Li Y, Wang X, Liao S, Yan H, Wu J, Lu Y, Zhai Y, Zhang J, Zhang H, Zhang H, Yang C, Cao P, Cheng S, Zhou G. The A-to-I editing of KPC1 promotes intrahepatic cholangiocarcinoma by attenuating proteasomal processing of NF-κB1 p105 to p50. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:338. [PMID: 36476255 PMCID: PMC9730630 DOI: 10.1186/s13046-022-02549-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Aberrant RNA editing of adenosine-to-inosine (A-to-I) has been linked to multiple human cancers, but its role in intrahepatic cholangiocarcinoma (iCCA) remains unknown. We conducted an exome-wide investigation to search for dysregulated RNA editing that drive iCCA pathogenesis. METHODS An integrative whole-exome and transcriptome sequencing analysis was performed to elucidate the RNA editing landscape in iCCAs. Putative RNA editing sites were validated by Sanger sequencing. In vitro and in vivo experiments were used to assess the effects of an exemplary target gene Kip1 ubiquitination-promoting complex 1 (KPC1) and its editing on iCCA cells growth and metastasis. Crosstalk between KPC1 RNA editing and NF-κB signaling was analyzed by molecular methods. RESULTS Through integrative omics analyses, we revealed an adenosine deaminases acting on RNA 1A (ADAR1)-mediated over-editing pattern in iCCAs. ADAR1 is frequently amplified and overexpressed in iCCAs and plays oncogenic roles. Notably, we identified a novel ADAR1-mediated A-to-I editing of KPC1 transcript, which results in substitution of methionine with valine at residue 8 (p.M8V). KPC1 p.M8V editing confers loss-of-function phenotypes through blunting the tumor-suppressive role of wild-type KPC1. Mechanistically, KPC1 p.M8V weakens the affinity of KPC1 to its substrate NF-κB1 p105, thereby reducing the ubiquitinating and proteasomal processing of p105 to p50, which in turn enhances the activity of oncogenic NF-κB signaling. CONCLUSIONS Our findings established that amplification-driven ADAR1 overexpression results in overediting of KPC1 p.M8V in iCCAs, leading to progression via activation of the NF-κB signaling pathway, and suggested ADAR1-KPC1-NF-κB axis as a potential therapeutic target for iCCA.
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Affiliation(s)
- Chengming Gao
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Guangming Zhou
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Jie Shi
- grid.414375.00000 0004 7588 8796Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, 225 Changhai Road, Shanghai, 200433 China
| | - Peipei Shi
- grid.256885.40000 0004 1791 4722Hebei University, Baoding City, China
| | - Liang Jin
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Yuanfeng Li
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Xiaowen Wang
- grid.419611.a0000 0004 0457 9072State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Song Liao
- grid.488137.10000 0001 2267 2324Medical School of Chinese PLA, Beijing, China
| | - Han Yan
- grid.256885.40000 0004 1791 4722Hebei University, Baoding City, China
| | - Junjie Wu
- grid.186775.a0000 0000 9490 772XAnhui Medical University, Hefei City, China
| | - Yiming Lu
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Yun Zhai
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Jinxu Zhang
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China ,grid.419611.a0000 0004 0457 9072State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Haitao Zhang
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Hongxing Zhang
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China ,grid.419611.a0000 0004 0457 9072State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Chenning Yang
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Pengbo Cao
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China
| | - Shuqun Cheng
- grid.414375.00000 0004 7588 8796Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, 225 Changhai Road, Shanghai, 200433 China
| | - Gangqiao Zhou
- grid.506261.60000 0001 0706 7839State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 China ,grid.256885.40000 0004 1791 4722Hebei University, Baoding City, China ,grid.186775.a0000 0000 9490 772XAnhui Medical University, Hefei City, China ,grid.89957.3a0000 0000 9255 8984Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing City, China
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Knockdown of RhoQ, a member of Rho GTPase, accelerates TGF-β-induced EMT in human lung adenocarcinoma. Biochem Biophys Rep 2022; 32:101346. [PMID: 36120491 PMCID: PMC9474329 DOI: 10.1016/j.bbrep.2022.101346] [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: 07/05/2022] [Revised: 08/30/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, and the most common subtype of lung cancer is adenocarcinoma. RhoQ is a Rho family GTPase with primary sequence and structural similarities to Cdc42 and RhoJ. RhoQ is involved in neurite outgrowth via membrane trafficking and is essential for insulin-stimulated glucose uptake in mature adipocytes. However, the function of RhoQ in lung adenocarcinoma (LUAD) remains unclear. In this study, RhoQ siRNAs were introduced into A549 and PC-9 cells. Expression level of EMT-related genes and invasion ability were investigated using Western blot and transwell assay. To examine the relationship between RhoQ expression and prognosis of LUAD, Kaplan–Meier plotter was used. We discovered that suppressing RhoQ expression promoted TGF-β-mediated EMT and invasion in LUAD cell lines. Furthermore, RhoQ knockdown increased Smad3 phosphorylation and Snail expression, indicating that RhoQ was involved in TGF/Smad signaling during the EMT process. Moreover, Kaplan–Meier plotter analysis revealed that low RhoQ levels were associated with poor overall survival in patients with LUAD. In conclusion, these findings shed light on RhoQ's role as a negative regulator of TGF-β-mediated EMT in LUAD.
Knockdown of RhoQ expression promoted TGF-β-mediated EMT and invasion in human lung adenocarcinoma cells. RhoQ knockdown increased Smad3 phosphorylation and Snail expression during the EMT process. Low RhoQ levels were associated with poor overall survival in patients with lung adenocarcinoma.
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29
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RNA modifications: importance in immune cell biology and related diseases. Signal Transduct Target Ther 2022; 7:334. [PMID: 36138023 PMCID: PMC9499983 DOI: 10.1038/s41392-022-01175-9] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/23/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
RNA modifications have become hot topics recently. By influencing RNA processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune cell abnormality in human diseases is also a research focus and progressing rapidly these years. Studies have demonstrated that RNA modifications participate in the multiple biological processes of immune cells, including development, differentiation, activation, migration, and polarization, thereby modulating the immune responses and are involved in some immune related diseases. In this review, we present existing knowledge of the biological functions and underlying mechanisms of RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, and adenosine-to-inosine (A-to-I) RNA editing, and summarize their critical roles in immune cell biology. Via regulating the biological processes of immune cells, RNA modifications can participate in the pathogenesis of immune related diseases, such as cancers, infection, inflammatory and autoimmune diseases. We further highlight the challenges and future directions based on the existing knowledge. All in all, this review will provide helpful knowledge as well as novel ideas for the researchers in this area.
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30
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Chen J, Li L, Liu TY, Fu HF, Lai YH, Lei X, Xu JF, Yu JS, Xia YJ, Zhang TH, Yang DJ, He YL. CPEB3 suppresses gastric cancer progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies. Oncogene 2022; 41:4591-4605. [PMID: 36068334 DOI: 10.1038/s41388-022-02454-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/09/2022]
Abstract
Deciphering the crosstalk between RNA-binding proteins and corresponding RNAs will provide a better understanding of gastric cancer (GC) progression. The comprehensive bioinformatics study identified cytoplasmic polyadenylation element-binding protein 3 (CPEB3) might play a vital role in GC progression. Then we found CPEB3 was downregulated in GC and correlated with prognosis. In addition, CPEB3 suppressed GC cell proliferation, invasion and migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistic study demonstrated CPEB3 interacted with 3'-UTR of ADAR1 mRNA through binding to CPEC nucleotide element, and then inhibited its translation by localizing it to processing bodies (P bodies), eventually leading to the suppression of ADAR1-mediated RNA editing. Microscale thermophoresis assay further revealed that the direct interaction between CPEB3 and GW182, the P-body's major component, was through the 440-698AA region of CPEB3 binding to the 403-860AA region of GW182. Finally, AAV9-CPEB3 was developed and administrated in mouse models to assess its potential value in gene therapy. We found AAV9-CPEB3 inhibited GC growth and metastasis. Besides, AAV9-CPEB3 induced hydropic degeneration in mouse liver, but did not cause kidney damage. These findings concluded that CPEB3 suppresses GC progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.
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Affiliation(s)
- Jian Chen
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Lu Li
- Department of Clinical Microbiology Laboratory, Institute of Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Tian-Yu Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hua-Feng Fu
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuan-Hui Lai
- Department of Thyroid and Breast Surgery, The Eastern Division of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiong Lei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jun-Fa Xu
- Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Ji-Shang Yu
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yu-Jian Xia
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tian-Hao Zhang
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dong-Jie Yang
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Yu-Long He
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. .,Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
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31
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Fu T, Chan TW, Bahn JH, Kim TH, Rowat AC, Xiao X. Multifaceted role of RNA editing in promoting loss-of-function of PODXL in cancer. iScience 2022; 25:104836. [PMID: 35992085 PMCID: PMC9382340 DOI: 10.1016/j.isci.2022.104836] [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: 05/12/2022] [Revised: 06/16/2022] [Accepted: 07/20/2022] [Indexed: 12/03/2022] Open
Abstract
PODXL, a protein that is dysregulated in multiple cancers, plays an important role in promoting cancer metastasis. In this study, we report that RNA editing promotes the inclusion of a PODXL alternative exon. The resulting edited PODXL long isoform is more prone to protease digestion and has the strongest effects on reducing cell migration and cisplatin chemoresistance among the three PODXL isoforms (short, unedited long, and edited long isoforms). Importantly, the editing level of the PODXL recoding site and the inclusion level of the PODXL alternative exon are strongly associated with overall patient survival in Kidney Renal Clear Cell Carcinoma (KIRC). Supported by significant enrichment of exonic RNA editing sites in alternatively spliced exons, we hypothesize that exonic RNA editing sites may enhance proteomic diversity through alternative splicing, in addition to amino acid changes, a previously under-appreciated aspect of RNA editing function.
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Affiliation(s)
- Ting Fu
- Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Tracey W. Chan
- Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jae Hoon Bahn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Tae-Hyung Kim
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Amy C. Rowat
- Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Xinshu Xiao
- Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
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32
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Ni X, Chen C, Cui G, Ding W, Liu J. Crosstalk of RNA Adenosine Modification-Related Subtypes, Establishment of a Prognostic Model, and Immune Infiltration Characteristics in Ovarian Cancer. Front Immunol 2022; 13:932876. [PMID: 35837397 PMCID: PMC9274011 DOI: 10.3389/fimmu.2022.932876] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 05/30/2022] [Indexed: 12/14/2022] Open
Abstract
Background Four RNA adenosine modifications, including m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, have been identified as potentially valuable in influencing colorectal carcinogenesis, immune infiltration, and response to drug therapy. However, the regulatory mechanisms and clinical significance of these four RNA modifications in ovarian cancer (OC) remain unknown. Methods We comprehensively described the transcriptional and genetic modifications of 26 RNA modification "writers" in OC and assessed the expression patterns. We identified two RNA modification subtypes using an unsupervised clustering approach. Subsequently, using differentially expressed genes (DEGs) in both subtypes, we calculated RNA modification "writer" scores (RMW scores) to characterize the RNA modifications of single OC patients. RMW score-related gene expression was investigated by qRT-PCR. We explored the correlation between RMW score and clinical features, immune infiltration, and drug sensitivity. We drew a nomogram to more intuitively and accurately describe the application value of the RMW score. Results We found that molecular alterations in "writers" are strongly related to prognostic and immune-infiltrating features in OC patients. We identified two different clusters of RNA modifications. According to the immune infiltration characteristics in the two RNA modification isoforms, cluster A and cluster B can correspond to "hot" and "cold" tumors, respectively. With the median RMW score, we classified the patients into high- and low-score subgroups. A low RMW score was associated with good patient prognosis and lower immune infiltration. In addition, a low RMW score equated with a higher cancer stem cell index and a lower tumor mutation burden, which to some extent affected the sensitivity of patients to therapeutic drugs. Seven RMW score-related gene expressions were investigated by qRT-PCR in three OC cell lines. Compared to previously known models, our established RMW score has higher accuracy in predicting patient survival. Conclusion A comprehensive analysis of four RNA modification patterns in OC reveals their potential value in OC prognosis, immune microenvironment, and drug sensitivity. These results could deepen our knowledge of RNA modification and yield fresh insights for new personalized therapeutic strategies.
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Affiliation(s)
- Xiaoge Ni
- Department of Obstetrics and Gynecology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Can Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guoliang Cui
- Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei Ding
- Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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33
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Wan J, Chen S, Zhang A, Liu Y, Zhang Y, Li Q, Yu Z, Wan Y, Yang L, Wang Q. Development and Validation of a Four Adenosine-to-Inosine RNA Editing Site-Relevant Prognostic Signature for Assessing Survival in Breast Cancer Patients. Front Oncol 2022; 12:861439. [PMID: 35494026 PMCID: PMC9039306 DOI: 10.3389/fonc.2022.861439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022] Open
Abstract
Background Adenosine-to-inosine RNA editing (ATIRE) is increasingly being used to characterize cancer. However, no studies have been conducted to identify an ATIRE signature for predicting cancer survival. Methods Breast cancer (BRCA) samples with ATIRE profiles from The Cancer Genome Atlas were divided into training (n = 452) and internal validation cohorts (n = 311), and 197 additional BRCA patients were recruited as an external validation cohort. The ATIRE signature for BRCA overall survival (OS) and disease-free survival (DFS) were identified using forest algorithm analysis and experimentally verified by direct sequencing. An ATIRE-based risk score (AIRS) was established with these selected ATIRE sites. Significantly prognostic factors were incorporated to generate a nomogram that was evaluated using Harrell’s C-index and calibration plot for all cohorts. Results Seven ATIRE sites were revealed to be associated with both BRCA OS and DFS, of which four sites were experimentally confirmed. Patients with high AIRS displayed a higher risk of death than those with low AIRS in the training (hazard ratio (HR) = 3.142, 95%CI = 1.932–5.111), internal validation (HR = 2.097, 95%CI = 1.123–3.914), and external validation cohorts (HR = 2.680, 95%CI = 1.000–7.194). A similar hazard effect of high AIRS on DFS was also observed. The nomogram yielded Harrell’s C-indexes of 0.816 (95%CI = 0.784–0.847), 0.742 (95%CI = 0.684–0.799), and 0.869 (95%CI = 0.835–0.902) for predicting OS and 0.767 (95%CI = 0.708–0.826), 0.684 (95%CI = 0.605–0.763), and 0.635 (95%CI = 0.566–0.705) for predicting DFS in the three cohorts. Conclusion AIRS nomogram could help to predict OS and DFS of patients with BRCA.
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Affiliation(s)
- Jian Wan
- The First Affiliated Hospital, Jinan University, Guangzhou, China.,Breast Disease Center, Guangdong Women and Children Hospital, Guangzhou, China
| | - Shizhen Chen
- The State Key Lab of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Anqin Zhang
- Breast Disease Center, Guangdong Women and Children Hospital, Guangzhou, China
| | - Yiting Liu
- Breast Disease Center, Guangdong Women and Children Hospital, Guangzhou, China
| | - Yangyang Zhang
- Breast Disease Center, Guangdong Women and Children Hospital, Guangzhou, China
| | - Qinghua Li
- Breast Disease Center, Guangdong Women and Children Hospital, Guangzhou, China
| | - Ziqi Yu
- The State Key Lab of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Yuwei Wan
- The State Key Lab of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Lei Yang
- The State Key Lab of Respiratory Disease, Institute of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Qi Wang
- The First Affiliated Hospital, Jinan University, Guangzhou, China.,Breast Disease Center, Guangdong Women and Children Hospital, Guangzhou, China
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34
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Lin SH, Chen SCC. RNA Editing in Glioma as a Sexually Dimorphic Prognostic Factor That Affects mRNA Abundance in Fatty Acid Metabolism and Inflammation Pathways. Cells 2022; 11:cells11071231. [PMID: 35406793 PMCID: PMC8997934 DOI: 10.3390/cells11071231] [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: 02/09/2022] [Revised: 03/16/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023] Open
Abstract
RNA editing alters the nucleotide sequence and has been associated with cancer progression. However, little is known about its prognostic and regulatory roles in glioma, one of the most common types of primary brain tumors. We characterized and analyzed RNA editomes of glioblastoma and isocitrate dehydrogenase mutated (IDH-MUT) gliomas from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas (CGGA). We showed that editing change during glioma progression was another layer of molecular alterations and that editing profiles predicted the prognosis of glioblastoma and IDH-MUT gliomas in a sex-dependent manner. Hyper-editing was associated with poor survival in females but better survival in males. Moreover, noncoding editing events impacted mRNA abundance of the host genes. Genes associated with inflammatory response (e.g., EIF2AK2, a key mediator of innate immunity) and fatty acid oxidation (e.g., acyl-CoA oxidase 1, the rate-limiting enzyme in fatty acid β-oxidation) were editing-regulated and associated with glioma progression. The above findings were further validated in CGGA samples. Establishment of the prognostic and regulatory roles of RNA editing in glioma holds promise for developing editing-based therapeutic strategies against glioma progression. Furthermore, sexual dimorphism at the epitranscriptional level highlights the importance of developing sex-specific treatments for glioma.
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35
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Jahid S, Ortega JA, Vuong LM, Acquistapace IM, Hachey SJ, Flesher JL, La Serra MA, Brindani N, La Sala G, Manigrasso J, Arencibia JM, Bertozzi SM, Summa M, Bertorelli R, Armirotti A, Jin R, Liu Z, Chen CF, Edwards R, Hughes CCW, De Vivo M, Ganesan AK. Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer. Cell Rep 2022; 39:110641. [PMID: 35385746 PMCID: PMC9127750 DOI: 10.1016/j.celrep.2022.110641] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/01/2022] [Accepted: 03/16/2022] [Indexed: 01/21/2023] Open
Abstract
CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here, we use computer-aided drug design to discover a chemical entity (ARN22089) that has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in 3D vascularized microtumor models (VMT) in vitro. Additionally, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. ARN22089 selectively blocks CDC42 effector interactions without affecting the binding between closely related GTPases and their downstream effectors. Taken together, we identify a class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.
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Affiliation(s)
- Sohail Jahid
- Department of Dermatology, University of California, Irvine, CA 92697, USA
| | - Jose A Ortega
- Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Linh M Vuong
- Department of Dermatology, University of California, Irvine, CA 92697, USA
| | - Isabella Maria Acquistapace
- Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Stephanie J Hachey
- Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA
| | - Jessica L Flesher
- Department of Biological Chemistry, University of California, Irvine, CA 92697, USA
| | - Maria Antonietta La Serra
- Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Nicoletta Brindani
- Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Giuseppina La Sala
- Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Jacopo Manigrasso
- Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Jose M Arencibia
- Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Sine Mandrup Bertozzi
- Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Maria Summa
- Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Rosalia Bertorelli
- Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Andrea Armirotti
- Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Rongsheng Jin
- Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA
| | - Zheng Liu
- Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA
| | - Chi-Fen Chen
- Department of Dermatology, University of California, Irvine, CA 92697, USA
| | - Robert Edwards
- Department of Pathology and Lab Medicine, University of California, Irvine, CA 92697, USA
| | - Christopher C W Hughes
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA
| | - Marco De Vivo
- Laboratory of Molecular Modeling and Drug Design, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
| | - Anand K Ganesan
- Department of Dermatology, University of California, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
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36
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Jiang L, Hao Y, Shao C, Wu Q, Prager BC, Gimple RC, Sulli G, Kim LJ, Zhang G, Qiu Z, Zhu Z, Fu XD, Rich JN. ADAR1-mediated RNA editing links ganglioside catabolism to glioblastoma stem cell maintenance. J Clin Invest 2022; 132:143397. [PMID: 35133980 PMCID: PMC8920333 DOI: 10.1172/jci143397] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 02/03/2022] [Indexed: 11/17/2022] Open
Abstract
Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, containing GBM stem cells (GSCs) that contribute to therapeutic resistance and relapse. Exposing potential GSC vulnerabilities may provide therapeutic strategies against GBM. Here, we interrogated the role of Adenosine-to-Inosine (A-to-I) RNA editing mediated by ADAR1 (adenosine deaminase acting on RNA 1) in GSCs and found that both ADAR1 and global RNA editomes were elevated in GSCs compared to normal neural stem cells (NSCs). ADAR1 inactivation or blocking the upstream JAK/STAT pathway through TYK2 inhibition impaired GSC self-renewal and stemness. Downstream of ADAR1, RNA editing of the 3'UTR of GM2A, a key ganglioside catabolism activator, proved to be critical, as interfering with ganglioside catabolism showed similar functional impact on GSCs as ADAR1 disruption. These findings reveal RNA editing links ganglioside catabolism to GSC self-renewal and stemness, exposing a potential vulnerability of GBM for therapeutic intervention.
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Affiliation(s)
- Li Jiang
- Department of Medicine, University of California, San Diego, San Diego, United States of America
| | - Yajing Hao
- Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States of America
| | - Changwei Shao
- Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States of America
| | - Qiulian Wu
- Hillman Cancer Center, Cancer Institute, University of Pittsburgh, Pittsburgh, United States of America
| | - Briana C Prager
- Stem Cell Biology, Cleveland Clinic, Cleveland, United States of America
| | - Ryan C Gimple
- Department of Medicine, University of California, San Diego, San Diego, United States of America
| | - Gabriele Sulli
- Department of Medicine, University of California, San Diego, San Diego, United States of America
| | - Leo Jk Kim
- Department of Medicine, University of California, San Diego, San Diego, United States of America
| | - Guoxin Zhang
- Department of Medicine, University of California, San Diego, San Diego, United States of America
| | - Zhixin Qiu
- Hillman Cancer Center, Cancer Institute, University of Pittsburgh, Pittsburgh, United States of America
| | - Zhe Zhu
- Department of Medicine, University of California, San Diego, San Diego, United States of America
| | - Xiang-Dong Fu
- Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States of America
| | - Jeremy N Rich
- Hillman Cancer Center, Cancer Institute, University of Pittsburgh, Pittsburgh, United States of America
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37
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Zhang S, Xiong Y, Zheng C, Long J, Zhou H, Zeng Z, Ouyang Y, Tang F. Crosstalk Between Four Types of RNA Modification Writers Characterizes the Tumor Immune Microenvironment Infiltration Patterns in Skin Cutaneous Melanoma. Front Cell Dev Biol 2022; 10:821678. [PMID: 35155433 PMCID: PMC8826580 DOI: 10.3389/fcell.2022.821678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
The “writers” of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification “writers” in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification “writer” scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these “writers” essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.
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Affiliation(s)
- Shichao Zhang
- Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Yu Xiong
- Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Chaochao Zheng
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Jinhua Long
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Houming Zhou
- Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
| | - Zhu Zeng
- Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
- *Correspondence: Fuzhou Tang, ; Yan Ouyang, ; Zhu Zeng,
| | - Yan Ouyang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
- *Correspondence: Fuzhou Tang, ; Yan Ouyang, ; Zhu Zeng,
| | - Fuzhou Tang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, China
- *Correspondence: Fuzhou Tang, ; Yan Ouyang, ; Zhu Zeng,
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38
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Amweg A, Tusup M, Cheng P, Picardi E, Dummer R, Levesque MP, French LE, Guenova E, Läuchli S, Kundig T, Mellett M, Pascolo S. The A to I editing landscape in melanoma and its relation to clinical outcome. RNA Biol 2022; 19:996-1006. [PMID: 35993275 PMCID: PMC9415457 DOI: 10.1080/15476286.2022.2110390] [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] [Indexed: 12/03/2022] Open
Abstract
RNA editing refers to non-transient RNA modifications that occur after transcription and prior to translation by the ribosomes. RNA editing is more widespread in cancer cells than in non-transformed cells and is associated with tumorigenesis of various cancer tissues. However, RNA editing can also generate neo-antigens that expose tumour cells to host immunosurveillance. Global RNA editing in melanoma and its relevance to clinical outcome currently remain poorly characterized. The present study compared RNA editing as well as gene expression in tumour cell lines from melanoma patients of short or long metastasis-free survival, patients relapsing or not after immuno- and targeted therapy and tumours harbouring BRAF or NRAS mutations. Overall, our results showed that NTRK gene expression can be a marker of resistance to BRAF and MEK inhibition and gives some insights of candidate genes as potential biomarkers. In addition, this study revealed an increase in Adenosine-to-Inosine editing in Alu regions and in non-repetitive regions, including the hyperediting of the MOK and DZIP3 genes in relapsed tumour samples during targeted therapy and of the ZBTB11 gene in NRAS mutated melanoma cells. Therefore, RNA editing could be a promising tool for identifying predictive markers, tumour neoantigens and targetable pathways that could help in preventing relapses during immuno- or targeted therapies.
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Affiliation(s)
- Austeja Amweg
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
| | - Marina Tusup
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
| | - Phil Cheng
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
| | - Ernesto Picardi
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari "A. Moro", Bari, Italy.,Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council, Bari, Italy
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
| | - Mitchell P Levesque
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
| | - Lars E French
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany.,Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Emmanuella Guenova
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland.,Department of Dermatology, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Severin Läuchli
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
| | - Thomas Kundig
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
| | - Mark Mellett
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
| | - Steve Pascolo
- Department of Dermatology, University Hospital Zürich (USZ), Zürich, Switzerland.,Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland
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39
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Song B, Shiromoto Y, Minakuchi M, Nishikura K. The role of RNA editing enzyme ADAR1 in human disease. WILEY INTERDISCIPLINARY REVIEWS. RNA 2022; 13:e1665. [PMID: 34105255 PMCID: PMC8651834 DOI: 10.1002/wrna.1665] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 03/02/2021] [Accepted: 04/22/2021] [Indexed: 12/19/2022]
Abstract
Adenosine deaminase acting on RNA (ADAR) catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA), which can lead to the creation of missense mutations in coding sequences. Recent studies show that editing-dependent functions of ADAR1 protect dsRNA from dsRNA-sensing molecules and inhibit innate immunity and the interferon-mediated response. Deficiency in these ADAR1 functions underlie the pathogenesis of autoinflammatory diseases such as the type I interferonopathies Aicardi-Goutieres syndrome and dyschromatosis symmetrica hereditaria. ADAR1-mediated editing of endogenous coding and noncoding RNA as well as ADAR1 editing-independent interactions with DICER can also have oncogenic or tumor suppressive effects that affect tumor proliferation, invasion, and response to immunotherapy. The combination of proviral and antiviral roles played by ADAR1 in repressing the interferon response and editing viral RNAs alters viral morphogenesis and cell susceptibility to infection. This review analyzes the structure and function of ADAR1 with a focus on its position in human disease pathways and the mechanisms of its disease-associated effects. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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Affiliation(s)
- Brian Song
- Department of Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Yusuke Shiromoto
- Department of Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Moeko Minakuchi
- Department of Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Kazuko Nishikura
- Department of Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania, USA
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40
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Chen J, Liu HF, Qiao LB, Wang FB, Wang L, Lin Y, Liu J. Global RNA editing identification and characterization during human pluripotent-to-cardiomyocyte differentiation. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:879-891. [PMID: 34760335 PMCID: PMC8551472 DOI: 10.1016/j.omtn.2021.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/05/2021] [Accepted: 10/01/2021] [Indexed: 01/19/2023]
Abstract
RNA editing is widely involved in stem cell differentiation and development; however, RNA editing events during human cardiomyocyte differentiation have not yet been characterized and elucidated. Here, we identified genome-wide RNA editing sites and systemically characterized their genomic distribution during four stages of human cardiomyocyte differentiation. It was found that the expression level of ADAR1 affected the global number of adenosine to inosine (A-to-I) editing sites but not the editing degree. Next, we identified 43, 163, 544, and 141 RNA editing sites that contribute to changes in amino acid sequences, variation in alternative splicing, alterations in miRNA-target binding, and changes in gene expression, respectively. Generally, RNA editing showed a stage-specific pattern with 211 stage-shared editing sites. Interestingly, cardiac muscle contraction and heart-disease-related pathways were enriched by cardio-specific editing genes, emphasizing the connection between cardiomyocyte differentiation and heart diseases from the perspective of RNA editing. Finally, it was found that these RNA editing sites are also related to several congenital and noncongenital heart diseases. Together, our study provides a new perspective on cardiomyocyte differentiation and offers more opportunities to understand the mechanisms underlying cell fate determination, which can promote the development of cardiac regenerative medicine and therapies for human heart diseases.
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Affiliation(s)
- Juan Chen
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China
| | - Hui-Fang Liu
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China
| | - Li-Bo Qiao
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China
| | - Fang-Bin Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China
| | - Lu Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China
| | - Yan Lin
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China
| | - Jian Liu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China.,Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei, Anhui 230009, China
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41
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Hülsemann M, Sanchez C, Verkhusha PV, Des Marais V, Mao SPH, Donnelly SK, Segall JE, Hodgson L. TC10 regulates breast cancer invasion and metastasis by controlling membrane type-1 matrix metalloproteinase at invadopodia. Commun Biol 2021; 4:1091. [PMID: 34531530 PMCID: PMC8445963 DOI: 10.1038/s42003-021-02583-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 08/23/2021] [Indexed: 01/12/2023] Open
Abstract
During breast cancer metastasis, cancer cell invasion is driven by actin-rich protrusions called invadopodia, which mediate the extracellular matrix degradation required for the success of the invasive cascade. In this study, we demonstrate that TC10, a member of a Cdc42 subfamily of p21 small GTPases, regulates the membrane type 1 matrix metalloproteinase (MT1-MMP)-driven extracellular matrix degradation at invadopodia. We show that TC10 is required for the plasma membrane surface exposure of MT1-MMP at these structures. By utilizing our Förster resonance energy transfer (FRET) biosensor, we demonstrate the p190RhoGAP-dependent regulation of spatiotemporal TC10 activity at invadopodia. We identified a pathway that regulates invadopodia-associated TC10 activity and function through the activation of p190RhoGAP and the downstream interacting effector Exo70. Our findings reveal the role of a previously unknown regulator of vesicular fusion at invadopodia, TC10 GTPase, in breast cancer invasion and metastasis.
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Affiliation(s)
- Maren Hülsemann
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Colline Sanchez
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Polina V Verkhusha
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Vera Des Marais
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Analytical Imaging Facility, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Serena P H Mao
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Sara K Donnelly
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Jeffrey E Segall
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Louis Hodgson
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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42
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Ramírez-Moya J, Miliotis C, Baker AR, Gregory RI, Slack FJ, Santisteban P. An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks. Mol Cancer 2021; 20:115. [PMID: 34496885 PMCID: PMC8424981 DOI: 10.1186/s12943-021-01401-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/03/2021] [Indexed: 11/10/2022] Open
Abstract
Background Adenosine deaminases acting on RNA (ADARs) modify many cellular RNAs by catalyzing the conversion of adenosine to inosine (A-to-I), and their deregulation is associated with several cancers. We recently showed that A-to-I editing is elevated in thyroid tumors and that ADAR1 is functionally important for thyroid cancer cell progression. The downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 deregulation in thyroid cancer remain, however, poorly defined. Methods We performed whole transcriptome sequencing to determine the consequences of ADAR1 deregulation for global gene expression, RNA splicing and editing. The effects of gene silencing or RNA editing were investigated by analyzing cell viability, proliferation, invasion and subnuclear localization, and by protein and gene expression analysis. Results We report an oncogenic function for CDK13 in thyroid cancer and identify a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. CDK13 was significantly over-edited (c.308A > G) in tumor samples and functional analysis revealed that this editing event promoted cancer cell hallmarks. Finally, we show that CDK13 editing increases the nucleolar abundance of the protein, and that this event might explain, at least partly, the global change in splicing produced by ADAR1 deregulation. Conclusions Overall, our data support A-to-I editing as an important pathway in cancer progression and highlight novel mechanisms that might be used therapeutically in thyroid and other cancers. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-021-01401-y.
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Affiliation(s)
- Julia Ramírez-Moya
- Instituto, de Investigaciones Biomédicas "Alberto Sols"; Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.,Department of Pathology, Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.,Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Departments of Biological Chemistry and Molecular Pharmacology, and Pediatrics, Harvard Medical School, Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Christos Miliotis
- Department of Pathology, Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Allison R Baker
- Department of Pathology, Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Richard I Gregory
- Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Departments of Biological Chemistry and Molecular Pharmacology, and Pediatrics, Harvard Medical School, Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA
| | - Frank J Slack
- Department of Pathology, Harvard Medical School Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Pilar Santisteban
- Instituto, de Investigaciones Biomédicas "Alberto Sols"; Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain. .,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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43
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Abstract
Epigenetic modifications have gained attention since they can be potentially changed with environmental stimuli and can be associated with adverse health outcomes. Epitranscriptome field has begun to attract attention with several aspects since RNA modifications have been linked with critical biological processes and implicated in diseases. Several RNA modifications have been identified as reversible indicating the dynamic features of modification which can be altered by environmental cues. Currently, we know more than 150 RNA modifications in different organisms and on different bases which are modified by various chemical groups. RNA editing, which is one of the RNA modifications, occurs after transcription, which results in RNA sequence different from its corresponding DNA sequence. Emerging evidence reveals the functions of RNA editing as well as the association between RNA editing and diseases. However, the RNA editing field is beginning to grow up and needs more empirical evidence in regard to disease and toxicology. Thus, this review aims to provide the current evidence-based studies on RNA editing modifying genes for genotoxicity and cancer. The review presented the association between environmental xenobiotics exposure and RNA editing modifying genes and focused on the association between the expression of RNA editing modifying genes and cancer. Furthermore, we discussed the future directions of scientific studies in the area of RNA modifications, especially in the RNA editing field, and provided a knowledge-based framework for further studies.
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Affiliation(s)
- Akin Cayir
- Vocational Health College, Canakkale Onsekiz Mart University, Canakkale, Turkey
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44
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Ding HY, Yang WY, Zhang LH, Li L, Xie F, Li HY, Chen XY, Tu Z, Li Y, Chen Y, Yang SY. 8-Chloro-Adenosine Inhibits Proliferation of MDA-MB-231 and SK-BR-3 Breast Cancer Cells by Regulating ADAR1/p53 Signaling Pathway. Cell Transplant 2021; 29:963689720958656. [PMID: 32907379 PMCID: PMC7784596 DOI: 10.1177/0963689720958656] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
8-Chloro-adenosine (8-Cl-Ado) has been shown to exhibit its antitumor activity by inducing apoptosis in human lung cancer A549 and H1299 cells or autophagy in chronic lymphocytic leukemia, and MDA-MB-231 and MCF-7 breast cancer cells. Adenosine deaminases acting on RNA 1 (ADAR1) is tightly associated with cancer development and progression. The aim of this study was to investigate the role of ADAR1 in the proliferation of MDA-MB-231 and SK-BR-3 breast cancer cell lines after 8-Cl-Ado exposure and its possible mechanisms. After 8-Cl-Ado exposure, CCK-8 assay was performed to determine the cell proliferation; flow cytometry was used to analyze the cell cycle profiles and apoptosis; and the protein levels of ADAR1, p53, p21, and cyclin D1 were measured by western blotting. The results showed that the cell proliferation was greatly inhibited, G1 cell cycle was arrested, and apoptosis was induced after 8-Cl-Ado exposure. ADAR1 and cyclin D1 protein levels were dramatically decreased, while p53 and p21 levels were increased after 8-Cl-Ado exposure. Moreover, the cell growth inhibition was rescued, apoptosis was reduced, and p53 and p21 protein levels were downregulated, while cyclin D1 was upregulated when cells were transfected with plasmids expressing ADAR1 proteins. More importantly, RNA-binding domain of ADAR1 is critical to the cell growth inhibition of breast cancer cells exposed to 8-Cl-Ado. Together, 8-Cl-Ado inhibits the cell proliferation, induces G1 phase arrest and apoptosis at least by targeting ADAR1/p53/p21 signaling pathway. The findings may provide us with insights into the role of ADAR1 in breast cancer progression and help us better understand the effects of 8-Cl-Ado in the treatment of breast cancer.
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Affiliation(s)
- Hong-Yue Ding
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Wan-Yong Yang
- Dongguan Waterfront Zone Central Hospital, Dongguan, Guangdong, China
| | - Li-Hong Zhang
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Li Li
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Feng Xie
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Hua-Yi Li
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Xiao-Yu Chen
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Zeng Tu
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Yi Li
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Yong Chen
- Department of Radiology and Intervention, The General Hospital of Ningxia Medical University, Yinchuan, China
| | - Sheng-Yong Yang
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
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Palaz F, Kalkan AK, Can Ö, Demir AN, Tozluyurt A, Özcan A, Ozsoz M. CRISPR-Cas13 System as a Promising and Versatile Tool for Cancer Diagnosis, Therapy, and Research. ACS Synth Biol 2021; 10:1245-1267. [PMID: 34037380 DOI: 10.1021/acssynbio.1c00107] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Over the past decades, significant progress has been made in targeted cancer therapy. In precision oncology, molecular profiling of cancer patients enables the use of targeted cancer therapeutics. However, current diagnostic methods for molecular analysis of cancer are costly and require sophisticated equipment. Moreover, targeted cancer therapeutics such as monoclonal antibodies and small-molecule drugs may cause off-target effects and they are available for only a minority of cancer driver proteins. Therefore, there is still a need for versatile, efficient, and precise tools for cancer diagnostics and targeted cancer treatment. In recent years, the CRISPR-based genome and transcriptome engineering toolbox has expanded rapidly. Particularly, the RNA-targeting CRISPR-Cas13 system has unique biochemical properties, making Cas13 a promising tool for cancer diagnosis, therapy, and research. Cas13-based diagnostic methods allow early detection and monitoring of cancer markers from liquid biopsy samples without the need for complex instrumentation. In addition, Cas13 can be used for targeted cancer therapy through degrading and manipulating cancer-associated transcripts with high efficiency and specificity. Moreover, Cas13-mediated programmable RNA manipulation tools offer invaluable opportunities for cancer research, identification of drug-resistance mechanisms, and discovery of novel therapeutic targets. Here, we review and discuss the current use and potential applications of the CRISPR-Cas13 system in cancer diagnosis, therapy, and research. Thus, researchers will gain a deep understanding of CRISPR-Cas13 technologies, which have the potential to be used as next-generation cancer diagnostics and therapeutics.
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Affiliation(s)
- Fahreddin Palaz
- Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey
| | | | - Özgür Can
- Department of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey
| | - Ayça Nur Demir
- Faculty of Medicine, Afyonkarahisar Health Sciences University, Afyonkarahisar 03100, Turkey
| | - Abdullah Tozluyurt
- Department of Medical Microbiology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey
| | - Ahsen Özcan
- Institute of Genetic Engineering and Biotechnology, TUBITAK Marmara Research Center, Kocaeli 41470, Turkey
| | - Mehmet Ozsoz
- Department of Biomedical Engineering, Near East University, 10 Mersin, Nicosia, Turkey
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Tai Tay DJ, Song Y, Peng B, Toh TB, Hooi L, Kaixin Toh DF, Hong H, Tang SJ, Han J, Gan WL, Man Chan TH, Krishna MS, Patil KM, Maraswami M, Loh TP, Dan YY, Zhou L, Bonney GK, Kah-Hoe Chow P, Chen G, Kai-Hua Chow E, Le MT, Chen L. Targeting RNA Editing of Antizyme Inhibitor 1: a Potential Oligonucleotide-Based Antisense Therapy for Cancer. Mol Ther 2021; 29:3258-3273. [PMID: 33974998 PMCID: PMC8571177 DOI: 10.1016/j.ymthe.2021.05.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 03/29/2021] [Accepted: 05/05/2021] [Indexed: 11/26/2022] Open
Abstract
Dysregulated adenosine-to-inosine (A-to-I) RNA editing is implicated in various cancers. However, no available RNA editing inhibitors have so far been developed to inhibit cancer-associated RNA editing events. Here, we decipher the RNA secondary structure of antizyme inhibitor 1 (AZIN1), one of the best-studied A-to-I editing targets in cancer, by locating its editing site complementary sequence (ECS) at the 3′ end of exon 12. Chemically modified antisense oligonucleotides (ASOs) that target the editing region of AZIN1 caused a substantial exon 11 skipping, whereas ECS-targeting ASOs effectively abolished AZIN1 editing without affecting splicing and translation. We demonstrate that complete 2′-O-methyl (2′-O-Me) sugar ring modification in combination with partial phosphorothioate (PS) backbone modification may be an optimal chemistry for editing inhibition. ASO3.2, which targets the ECS, specifically inhibits cancer cell viability in vitro and tumor incidence and growth in xenograft models. Our results demonstrate that this AZIN1-targeting, ASO-based therapeutics may be applicable to a wide range of tumor types.
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Affiliation(s)
- Daryl Jin Tai Tay
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599
| | - Yangyang Song
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599
| | - Boya Peng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600; Department of Biomedical Sciences, School of Veterinary Medicine and Life Sciences, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong
| | - Tan Boon Toh
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; The N.1 Institute for Health (N.1), 28 Medical Dr, Singapore 117456
| | - Lissa Hooi
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599
| | - Desiree-Faye Kaixin Toh
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 21 Nanyang Link, Singapore 637371
| | - HuiQi Hong
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore 117593
| | - Sze Jing Tang
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599
| | - Jian Han
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599
| | - Wei Liang Gan
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599
| | - Tim Hon Man Chan
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599
| | - Manchugondanahalli S Krishna
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 21 Nanyang Link, Singapore 637371
| | - Kiran M Patil
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 21 Nanyang Link, Singapore 637371
| | - Manikantha Maraswami
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 21 Nanyang Link, Singapore 637371
| | - Teck Peng Loh
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 21 Nanyang Link, Singapore 637371
| | - Yock Young Dan
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228
| | - Lei Zhou
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228
| | - Glenn Kunnath Bonney
- Division of Hepatobiliary and Liver Transplantation Surgery, National University Health System, Singapore 119228
| | - Pierce Kah-Hoe Chow
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore 169610; Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore 169608; Duke-NUS Medical School, Singapore 169857
| | - Gang Chen
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 21 Nanyang Link, Singapore 637371
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600; The N.1 Institute for Health (N.1), 28 Medical Dr, Singapore 117456
| | - Minh Tn Le
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600; Department of Biomedical Sciences, School of Veterinary Medicine and Life Sciences, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong
| | - Leilei Chen
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, Singapore 117594.
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Destefanis E, Avşar G, Groza P, Romitelli A, Torrini S, Pir P, Conticello SG, Aguilo F, Dassi E. A mark of disease: how mRNA modifications shape genetic and acquired pathologies. RNA (NEW YORK, N.Y.) 2021; 27:367-389. [PMID: 33376192 PMCID: PMC7962492 DOI: 10.1261/rna.077271.120] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.
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Affiliation(s)
- Eliana Destefanis
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy
- The EPITRAN COST Action Consortium, COST Action CA16120
| | - Gülben Avşar
- The EPITRAN COST Action Consortium, COST Action CA16120
- Department of Bioengineering, Gebze Technical University, 41400 Kocaeli, Turkey
| | - Paula Groza
- The EPITRAN COST Action Consortium, COST Action CA16120
- Department of Medical Biosciences, Umeå University, 901 87 Umeå, Sweden
- Wallenberg Center for Molecular Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Antonia Romitelli
- The EPITRAN COST Action Consortium, COST Action CA16120
- Core Research Laboratory, ISPRO-Institute for Cancer Research, Prevention and Clinical Network, 50139 Firenze, Italy
- Department of Medical Biotechnologies, Università di Siena, 53100 Siena, Italy
| | - Serena Torrini
- The EPITRAN COST Action Consortium, COST Action CA16120
- Core Research Laboratory, ISPRO-Institute for Cancer Research, Prevention and Clinical Network, 50139 Firenze, Italy
- Department of Medical Biotechnologies, Università di Siena, 53100 Siena, Italy
| | - Pınar Pir
- The EPITRAN COST Action Consortium, COST Action CA16120
- Department of Bioengineering, Gebze Technical University, 41400 Kocaeli, Turkey
| | - Silvestro G Conticello
- The EPITRAN COST Action Consortium, COST Action CA16120
- Core Research Laboratory, ISPRO-Institute for Cancer Research, Prevention and Clinical Network, 50139 Firenze, Italy
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
| | - Francesca Aguilo
- The EPITRAN COST Action Consortium, COST Action CA16120
- Department of Medical Biosciences, Umeå University, 901 87 Umeå, Sweden
- Wallenberg Center for Molecular Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Erik Dassi
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy
- The EPITRAN COST Action Consortium, COST Action CA16120
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Zengin T, Önal-Süzek T. Comprehensive Profiling of Genomic and Transcriptomic Differences between Risk Groups of Lung Adenocarcinoma and Lung Squamous Cell Carcinoma. J Pers Med 2021; 11:154. [PMID: 33672117 PMCID: PMC7926392 DOI: 10.3390/jpm11020154] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/11/2021] [Accepted: 02/19/2021] [Indexed: 12/17/2022] Open
Abstract
Lung cancer is the second most frequently diagnosed cancer type and responsible for the highest number of cancer deaths worldwide. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are subtypes of non-small-cell lung cancer which has the highest frequency of lung cancer cases. We aimed to analyze genomic and transcriptomic variations including simple nucleotide variations (SNVs), copy number variations (CNVs) and differential expressed genes (DEGs) in order to find key genes and pathways for diagnostic and prognostic prediction for lung adenocarcinoma and lung squamous cell carcinoma. We performed a univariate Cox model and then lasso-regularized Cox model with leave-one-out cross-validation using The Cancer Genome Atlas (TCGA) gene expression data in tumor samples. We generated 35- and 33-gene signatures for prognostic risk prediction based on the overall survival time of the patients with LUAD and LUSC, respectively. When we clustered patients into high- and low-risk groups, the survival analysis showed highly significant results with high prediction power for both training and test datasets. Then, we characterized the differences including significant SNVs, CNVs, DEGs, active subnetworks, and the pathways. We described the results for the risk groups and cancer subtypes separately to identify specific genomic alterations between both high-risk groups and cancer subtypes. Both LUAD and LUSC high-risk groups have more downregulated immune pathways and upregulated metabolic pathways. On the other hand, low-risk groups have both up- and downregulated genes on cancer-related pathways. Both LUAD and LUSC have important gene alterations such as CDKN2A and CDKN2B deletions with different frequencies. SOX2 amplification occurs in LUSC and PSMD4 amplification in LUAD. EGFR and KRAS mutations are mutually exclusive in LUAD samples. EGFR, MGA, SMARCA4, ATM, RBM10, and KDM5C genes are mutated only in LUAD but not in LUSC. CDKN2A, PTEN, and HRAS genes are mutated only in LUSC samples. The low-risk groups of both LUAD and LUSC tend to have a higher number of SNVs, CNVs, and DEGs. The signature genes and altered genes have the potential to be used as diagnostic and prognostic biomarkers for personalized oncology.
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Affiliation(s)
- Talip Zengin
- Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, 48000 Muğla, Turkey;
- Department of Bioinformatics, Muğla Sıtkı Koçman University, 48000 Muğla, Turkey
| | - Tuğba Önal-Süzek
- Department of Bioinformatics, Muğla Sıtkı Koçman University, 48000 Muğla, Turkey
- Department of Computer Engineering, Muğla Sıtkı Koçman University, 48000 Muğla, Turkey
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49
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Kurkowiak M, Arcimowicz Ł, Chruściel E, Urban-Wójciuk Z, Papak I, Keegan L, O'Connell M, Kowalski J, Hupp T, Marek-Trzonkowska N. The effects of RNA editing in cancer tissue at different stages in carcinogenesis. RNA Biol 2021; 18:1524-1539. [PMID: 33593231 PMCID: PMC8582992 DOI: 10.1080/15476286.2021.1877024] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
RNA editing is one of the most prevalent and abundant forms of post-transcriptional RNA modification observed in normal physiological processes and often aberrant in diseases including cancer. RNA editing changes the sequences of mRNAs, making them different from the source DNA sequence. Edited mRNAs can produce editing-recoded protein isoforms that are functionally different from the corresponding genome-encoded protein isoforms. The major type of RNA editing in mammals occurs by enzymatic deamination of adenosine to inosine (A-to-I) within double-stranded RNAs (dsRNAs) or hairpins in pre-mRNA transcripts. Enzymes that catalyse these processes belong to the adenosine deaminase acting on RNA (ADAR) family. The vast majority of knowledge on the RNA editing landscape relevant to human disease has been acquired using in vitro cancer cell culture models. The limitation of such in vitro models, however, is that the physiological or disease relevance of results obtained is not necessarily obvious. In this review we focus on discussing in vivo occurring RNA editing events that have been identified in human cancer tissue using samples surgically resected or clinically retrieved from patients. We discuss how RNA editing events occurring in tumours in vivo can identify pathological signalling mechanisms relevant to human cancer physiology which is linked to the different stages of cancer progression including initiation, promotion, survival, proliferation, immune escape and metastasis.
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Affiliation(s)
- Małgorzata Kurkowiak
- International Centre for Cancer Vaccine Science (ICCVS), University of Gdańsk, Gdańsk, Poland
| | - Łukasz Arcimowicz
- International Centre for Cancer Vaccine Science (ICCVS), University of Gdańsk, Gdańsk, Poland
| | - Elżbieta Chruściel
- International Centre for Cancer Vaccine Science (ICCVS), University of Gdańsk, Gdańsk, Poland
| | - Zuzanna Urban-Wójciuk
- International Centre for Cancer Vaccine Science (ICCVS), University of Gdańsk, Gdańsk, Poland
| | - Ines Papak
- International Centre for Cancer Vaccine Science (ICCVS), University of Gdańsk, Gdańsk, Poland
| | - Liam Keegan
- CEITEC Masaryk University, Brno, CZ, Czech Republic
| | | | - Jacek Kowalski
- International Centre for Cancer Vaccine Science (ICCVS), University of Gdańsk, Gdańsk, Poland.,Department of Pathomorphology, Medical University of Gdańsk, Gdańsk, Poland
| | - Ted Hupp
- International Centre for Cancer Vaccine Science (ICCVS), University of Gdańsk, Gdańsk, Poland.,University of Edinburgh, Edinburgh Cancer Research Centre, Edinburgh, Scotland, UK
| | - Natalia Marek-Trzonkowska
- International Centre for Cancer Vaccine Science (ICCVS), University of Gdańsk, Gdańsk, Poland.,Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, Gdańsk, Poland
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50
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Chen H, Yao J, Bao R, Dong Y, Zhang T, Du Y, Wang G, Ni D, Xun Z, Niu X, Ye Y, Li HB. Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer. Mol Cancer 2021; 20:29. [PMID: 33557837 PMCID: PMC7869236 DOI: 10.1186/s12943-021-01322-w] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/22/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the "writer" enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these "writers" in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. METHODS We systematically characterized mRNA expression and genetic alterations of 26 RNA modification "writers" in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification "writers". Subsequently, we constructed the RNA modification "writer" Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. RESULTS We demonstrated that multi-layer alterations of RNA modification "writer" are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these "writers" to aid the clinical benefits of immunotherapy. CONCLUSIONS Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification "writers" in cancer therapy.
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Affiliation(s)
- Huifang Chen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Jiameng Yao
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Rujuan Bao
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Yu Dong
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Ting Zhang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Yanhua Du
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Gaoyang Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Duan Ni
- The Charles Perkins Centre, University of Sydney, Sydney, NSW 2006 Australia
| | - Zhenzhen Xun
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Xiaoyin Niu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Youqiong Ye
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Hua-Bing Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
- Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
- Department of Liver Surgery, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127 China
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