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Molecular Cancer Mar 2023Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes tumor cell... (Review)
Review
Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes tumor cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 and CD73 play critical roles in reshaping an immunosuppressive TME. The accumulated extracellular adenosine mediates its regulatory functions by binding to one of four adenosine receptors (A1R, A2AR, A2BR and A3R). The A2AR elicits its profound immunosuppressive function via regulating cAMP signaling. The increasing evidence suggests that CD39, CD73 and A2AR could be used as novel therapeutic targets for manipulating the antitumor immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting the CD39/CD73/A2AR pathway have been investigated in clinical trials as single agents or in combination with anti-PD-1/PD-L1 therapies. In this review, we provide an updated summary about the pathophysiological function of the adenosinergic pathway in cancer development, metastasis and drug resistance. The targeting of one or more components of the adenosinergic pathway for cancer therapy and circumvention of immunotherapy resistance are also discussed. Emerging biomarkers that may be used to guide the selection of CD39/CD73/A2AR-targeting treatment strategies for individual cancer patients is also deliberated.
Topics: Humans; Immunotherapy; Adenosine; Antibodies, Monoclonal; Cell Membrane; Neoplasms
PubMed: 36859386
DOI: 10.1186/s12943-023-01733-x -
Journal of Hematology & Oncology May 2022N-methylguanosine (m7G), one of the most prevalent RNA modifications, has recently attracted significant attention. The m7G modification actively participates in... (Review)
Review
N-methylguanosine (m7G), one of the most prevalent RNA modifications, has recently attracted significant attention. The m7G modification actively participates in biological and pathological functions by affecting the metabolism of various RNA molecules, including messenger RNA, ribosomal RNA, microRNA, and transfer RNA. Increasing evidence indicates a critical role for m7G in human disease development, especially cancer, and aberrant m7G levels are closely associated with tumorigenesis and progression via regulation of the expression of multiple oncogenes and tumor suppressor genes. Currently, the underlying molecular mechanisms of m7G modification in cancer are not comprehensively understood. Here, we review the current knowledge regarding the potential function of m7G modifications in cancer and discuss future m7G-related diagnostic and therapeutic strategies.
Topics: Guanosine; Humans; MicroRNAs; Neoplasms; RNA, Messenger
PubMed: 35590385
DOI: 10.1186/s13045-022-01285-5 -
Molecular Cancer May 2020N6-methyladenosine (m6A) is considered the most common, abundant, and conserved internal transcript modification, especially in eukaryotic messenger RNA (mRNA). m6A is... (Review)
Review
N6-methyladenosine (m6A) is considered the most common, abundant, and conserved internal transcript modification, especially in eukaryotic messenger RNA (mRNA). m6A is installed by m6A methyltransferases (METTL3/14, WTAP, RBM15/15B, VIRMA and ZC3H13, termed "writers"), removed by demethylases (FTO, ALKBH5, and ALKBH3, termed "erasers"), and recognized by m6A-binding proteins (YTHDC1/2, YTHDF1/2/3, IGF2BP1/2/3, HNRNP, and eIF3, termed "readers"). Accumulating evidence suggests that m6A RNA methylation greatly impacts RNA metabolism and is involved in the pathogenesis of many kinds of diseases, including cancers. In this review, we focus on the physiological functions of m6A modification and its related regulators, as well as on the potential biological roles of these elements in human tumors.
Topics: Adenosine; Animals; Biomarkers, Tumor; DNA Methylation; Disease Progression; Epigenesis, Genetic; Humans; Methyltransferases; Neoplasms
PubMed: 32398132
DOI: 10.1186/s12943-020-01204-7 -
The EMBO Journal Feb 2021RNA carries a diverse array of chemical modifications that play important roles in the regulation of gene expression. N -methyladenosine (m A), installed onto mRNA by... (Review)
Review
RNA carries a diverse array of chemical modifications that play important roles in the regulation of gene expression. N -methyladenosine (m A), installed onto mRNA by the METTL3/METTL14 methyltransferase complex, is the most prevalent mRNA modification. m A methylation regulates gene expression by influencing numerous aspects of mRNA metabolism, including pre-mRNA processing, nuclear export, decay, and translation. The importance of m A methylation as a mode of post-transcriptional gene expression regulation is evident in the crucial roles m A-mediated gene regulation plays in numerous physiological and pathophysiological processes. Here, we review current knowledge on the mechanisms by which m A exerts its functions and discuss recent advances that underscore the multifaceted role of m A in the regulation of gene expression. We highlight advances in our understanding of the regulation of m A deposition on mRNA and its context-dependent effects on mRNA decay and translation, the role of m A methylation of non-coding chromosomal-associated RNA species in regulating transcription, and the activities of the RNA demethylase FTO on diverse substrates. We also discuss emerging evidence for the therapeutic potential of targeting m A regulators in disease.
Topics: Adenosine; Animals; Humans; Methyltransferases; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 33470439
DOI: 10.15252/embj.2020105977 -
Signal Transduction and Targeted Therapy Sep 2022RNA modifications have become hot topics recently. By influencing RNA processes, including generation, transportation, function, and metabolization, they act as critical... (Review)
Review
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 N-methyladenosine (mA), 5-methylcytosine (mC), N-methyladenosine (mA), N-methylguanosine (mG), N-acetylcytosine (acC), 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.
Topics: 5-Methylcytosine; Adenosine; Humans; Inosine; Pseudouridine; RNA
PubMed: 36138023
DOI: 10.1038/s41392-022-01175-9 -
Molecular Plant Jan 2020Advances in the detection and mapping of messenger RNA (mRNA) N-methyladenosine (mA) and 5-methylcytosine (mC), and DNA N-methyldeoxyadenosine (6mA) redefined our... (Review)
Review
Advances in the detection and mapping of messenger RNA (mRNA) N-methyladenosine (mA) and 5-methylcytosine (mC), and DNA N-methyldeoxyadenosine (6mA) redefined our understanding of these modifications as additional tiers of epigenetic regulation. In plants, the most prevalent internal mRNA modifications, mA and mC, play crucial and dynamic roles in many processes, including embryo development, stem cell fate determination, trichome branching, leaf morphogenesis, floral transition, stress responses, fruit ripening, and root development. The newly identified and widespread epigenetic marker 6mA DNA methylation is associated with gene expression, plant development, and stress responses. Here, we review the latest research progress on mRNA and DNA epigenetic modifications, including the detection, dynamics, distribution, functions, regulatory proteins, and evolution, with a focus on mA, mC, and 6mA. We also provide some perspectives on future research of the newly identified and unknown epigenetic modifications of mRNA and DNA in plants.
Topics: 5-Methylcytosine; Adenosine; DNA Methylation; Epigenesis, Genetic; Plants; RNA, Messenger
PubMed: 31863849
DOI: 10.1016/j.molp.2019.12.007 -
Cancer Cell Mar 2020N-Methyladenosine (mA) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible... (Review)
Review
N-Methyladenosine (mA) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, mA affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we review the up-to-date knowledge of the pathological roles and underlying molecular mechanism of mA modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance, and discuss the therapeutic potential of targeting mA regulators for cancer therapy.
Topics: Adenosine; Epigenesis, Genetic; Female; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Male; Mutation; Neoplasms; RNA, Messenger; RNA, Untranslated
PubMed: 32183948
DOI: 10.1016/j.ccell.2020.02.004 -
Molecular Cancer Jan 2022N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in... (Review)
Review
N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in recent years. M6A plays multifunctional roles in normal and abnormal biological processes, and its role may vary greatly depending on the position of the m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis and ferroptosis, most of which involve the breakdown of the plasma membrane. Based on the implications of m6A methylation on PCD, the regulators and functional roles of m6A methylation were comprehensively studied and reported. In this review, we focus on the high-complexity links between m6A and different types of PCD pathways, which are then closely associated with the initiation, progression and resistance of cancer. Herein, clarifying the relationship between m6A and PCD is of great significance to provide novel strategies for cancer treatment, and has a great potential prospect of clinical application.
Topics: Adenosine; Apoptosis; Humans; Methylation; Neoplasms
PubMed: 35090469
DOI: 10.1186/s12943-022-01508-w -
Annual Review of Immunology Apr 2023Characterization of RNA modifications has identified their distribution features and molecular functions. Dynamic changes in RNA modification on various forms of RNA are... (Review)
Review
Characterization of RNA modifications has identified their distribution features and molecular functions. Dynamic changes in RNA modification on various forms of RNA are essential for the development and function of the immune system. In this review, we discuss the value of innovative RNA modification profiling technologies to uncover the function of these diverse, dynamic RNA modifications in various immune cells within healthy and diseased contexts. Further, we explore our current understanding of the mechanisms whereby aberrant RNA modifications modulate the immune milieu of the tumor microenvironment and point out outstanding research questions.
Topics: Humans; Animals; Adenosine; RNA; Immune System
PubMed: 37126422
DOI: 10.1146/annurev-immunol-101921-045401 -
International Journal of Molecular... Dec 2020N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types of RNA,... (Review)
Review
N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types of RNA, including mRNAs, rRNAs, tRNAs, long non‑coding RNAs and microRNAs, are involved in m6A methylation. The biological function of m6A modification is dynamically and reversibly mediated by methyltransferases (writers), demethylases (erasers) and m6A binding proteins (readers). The methyltransferase complex is responsible for the catalyzation of m6A modification and is typically made up of methyltransferase‑like (METTL)3, METTL14 and Wilms tumor 1‑associated protein. Erasers remove methylation by fat mass and obesity‑associated protein and ALKB homolog 5. Readers play a role through the recognition of m6A‑modified targeted RNA. The YT521‑B homology domain family, heterogeneous nuclear ribonucleoprotein and insulin‑like growth factor 2 mRNA‑binding protein serve as m6A readers. The m6A methylation on transcripts plays a pivotal role in the regulation of downstream molecular events and biological functions, such as RNA splicing, transport, stability and translatability at the post‑transcriptional level. The dysregulation of m6A modification is associated with cancer, drug resistance, virus replication and the pluripotency of embryonic stem cells. Recently, a number of studies have identified aberrant m6A methylation in cardiovascular diseases (CVDs), including cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification and pulmonary hypertension. The aim of the present review article was to summarize the recent research progress on the role of m6A modification in CVD and give a brief perspective on its prospective applications in CVD.
Topics: Adenosine; Animals; Cardiovascular Diseases; Humans; Methylation; Polymorphism, Single Nucleotide; RNA; RNA-Binding Proteins
PubMed: 33125109
DOI: 10.3892/ijmm.2020.4746