RNA modifications: importance in immune cell biology and related diseases

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 22, 2022

RNA modifications have become hot topics recently. By influencing processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune abnormality in human diseases is also a research focus progressing rapidly these years. Studies demonstrated that participate the multiple biological processes cells, development, differentiation, activation, migration, polarization, thereby modulating responses are involved some related diseases. In this review, we present existing knowledge functions underlying mechanisms modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) editing, summarize their roles Via regulating can pathogenesis diseases, such cancers, infection, inflammatory autoimmune We further highlight challenges future directions based on knowledge. All all, review will provide helpful well novel ideas for researchers area.

Language: Английский

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Small RNA modifications: regulatory molecules and potential applications

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: June 22, 2023

Abstract Small RNAs (also referred to as small noncoding RNAs, sncRNA) are defined polymeric ribonucleic acid molecules that less than 200 nucleotides in length and serve a variety of essential functions within cells. RNA species include microRNA (miRNA), PIWI-interacting (piRNA), interfering (siRNA), tRNA-derived (tsRNA), etc. Current evidence suggest can also have diverse modifications their nucleotide composition affect stability well capacity for nuclear export, these relevant drive molecular signaling processes biogenesis, cell proliferation differentiation. In this review, we highlight the characteristics cellular modifications, current techniques reliable detection. We discuss how may be clinical applications diagnosis treatment human health conditions such cancer.

Language: Английский

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Smoking‐Induced M2‐TAMs, via circEML4 in EVs, Promote the Progression of NSCLC through ALKBH5‐Regulated m6A Modification of SOCS2 in NSCLC Cells

Advanced Science, Journal Year: 2023, Volume and Issue: 10(22)

Published: May 28, 2023

Abstract Lung cancer is a commonly diagnosed disease worldwide, with non‐small cell lung cancers (NSCLCs) accounting for ≈ 85% of cases. Cigarette smoke an environmental exposure promoting progression NSCLC, but its role poorly understood. This study reports that smoking‐induced accumulation M2‐type tumor‐associated macrophages (M2‐TAMs) surrounding NSCLC tissues promotes malignancy. Specifically, extracellular vesicles (EVs) from cigarette extract (CSE)‐induced M2 promoted malignancy cells in vitro and vivo. circEML4 EVs CSE‐induced transported to cells, where it reduced the distribution ALKBH5 nucleus by interacting Human AlkB homolog H5 (ALKBH5), resulting elevated N6‐methyladenosine (m6A) modifications. m6A‐seq RNA‐seq revealed suppressor cytokine signaling 2 (SOCS2)‐mediated activation Janus kinase‐signal transducer activator transcription (JAK‐STAT) pathway regulating m6A modification SOCS2 via ALKBH5. Down‐regulation reversed EVs‐enhanced tumorigenicity metastasis cells. Furthermore, this found smoking patients showed increase circEML4‐positive M2‐TAMs. These results indicate M2‐TAMs promote through ALKBH5‐regulated SOCS2. also reveals TAMs acts as diagnostic biomarker especially history.

Language: Английский

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Epigenetics-targeted drugs: current paradigms and future challenges

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Language: Английский

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ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 15, 2025

The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role tumorigenesis and cancer progression. However, the detailed biological functions underlying mechanisms of m6A regulation gastric (GC) are poorly understood. Our research revealed that demethylase ALKBH5 was markedly downregulated GC tissues, which associated with poor patient prognosis. Functional studies demonstrated suppressing expression enhanced cell proliferation, migration, invasion. Mechanistically, removed modifications from 5' uncapped polyadenylated transcripts (UPTs) WRAP53. This demethylation decreased WRAP53 stability translation efficiency. lower level disrupts interaction between USP6 RALBP1 protein, promoting degradation thereby PI3K/Akt/mTOR signaling cascade, ultimately attenuating progression GC. These findings highlight pivotal ALKBH5-mediated inhibiting potential promising biomarker therapeutic target for intervention.

Language: Английский

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ALKBH5-Mediated m6A Demethylation of GLUT4 mRNA Promotes Glycolysis and Resistance to HER2-Targeted Therapy in Breast Cancer

Cancer Research, Journal Year: 2022, Volume and Issue: 82(21), P. 3974 - 3986

Published: Sept. 7, 2022

Abstract Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer HER2-positive tumors. Through global mass spectrometry–based proteomics approach, we discovered that expression N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in therapy-resistant cells. Elevated sufficient confer resistance therapy, and specific knockdown rescued efficacy trastuzumab lapatinib resistant Mechanistically, promoted m6A demethylation GLUT4 mRNA increased stability YTHDF2-dependent manner, resulting enhanced glycolysis In tissues obtained from poor response or observed associated prognosis patients. Moreover, suppression via genetic pharmacologic targeting inhibitor profoundly restored cells lapatinib, both vitro vivo. conclusion, ALKBH5-mediated promotes ALKBH5/GLUT4 axis has therapeutic potential treating refractory therapies. Significance: upregulation by induces target cancer.

Language: Английский

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ALKBH5‐mediated m⁶A demethylation of TIRAP mRNA promotes radiation‐induced liver fibrosis and decreases radiosensitivity of hepatocellular carcinoma

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(2)

Published: Feb. 1, 2023

Radiation-induced hepatic stellate cell (HSC) activation promotes radiation-induced liver fibrosis (RILF), a complication for hepatocellular carcinoma (HCC) radiotherapy. The demethylase alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) decreases N6-methyladenylate methylation (m6 A) modification of RNA, while its role in regulating RILF pathogenesis and HCC radiosensitivity remains unknown.Methylated RNA immunoprecipitation sequencing (MeRIP-seq) RNA-sequencing (RNA-seq) were used to screen target genes regulated by ALKBH5. HSC with altered ALKBH5 expression was assess irradiation-induced the effect on recruitment polarisation monocytes. Key cytokines medium from irradiated HSC-educated monocytes identified cytokine array detection. effects blocking key also evaluated.Radiation-induced mediated m6 A demethylation toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) mRNA activated downstream NF-κB JNK/Smad2 pathways promote activation. Additionally, CCL5 secretion monocyte M2 macrophage polarisation. Notably, polarised secreted CCL20 up-regulate HSC, reduce activating ALKBH5/TIRAP axis cells. knockdown-combined CCR6 (CCL20 receptor) inhibitor significantly alleviated improved mice. patients high TIRAP prone injury poor tumour response radiotherapy.Collectively, irradiation up-regulates mediate form positive feedback radiosensitivity. dual roles as microenvironmental regulator radiosensitisation provide new ideas prevention HCC.

Language: Английский

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Chemical Inhibitors Targeting the Oncogenic m⁶A Modifying Proteins

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(21), P. 3010 - 3022

Published: Oct. 27, 2023

ConspectusEpigenetics is brought to RNA, introducing a new dimension gene expression regulation. Among numerous RNA modifications, N6-methyladenosine (m6A) an abundant internal modification on eukaryote mRNA first identified in the 1970s. However, significance of m6A had been long neglected until fat mass and obesity-associated (FTO) enzyme was as demethylase almost 40 years later. The influences nearly every step metabolism thus broadly affects at multiple levels, playing critical role many biological processes, including cancer progression, metastasis, immune evasion. level dynamically regulated by epigenetic machinery comprising methyltransferases such methyltransferase-like protein 3 (METTL3), demethylases FTO AlkB human homologue 5 (ALKBH5), reader proteins. understanding biology epigenetics its translational drug discovery still infancy. It essential further develop chemical probes lead compounds for in-depth investigation into anticancer drugs targeting modifying oncogenic proteins.In this Account, we present our work development inhibitors regulate demethylase, elucidation their mode action. We reported rhein be substrate competitive inhibitor. Due rhein's poor selectivity, meclofenamic acid (MA) that selectively inhibits compared with ALKBH5. Based structural complex MA bound FTO, designed analogs FB23-2 Dac51, which exhibit significantly improved activities MA. For example, specific inhibition vitro among over 400 other proteins, kinases, proteases, DNA histone Mimicking depletion, promotes differentiation/apoptosis acute myeloid leukemia (AML) cells progression primary xenotransplanted mice. Dac51 treatment impairs glycolytic activity tumor restores function CD8+ T cells, thereby inhibiting growth solid tumors vivo. These were will continue used promote studies target discovery.Toward end, also include brief review ALKBH5 METTL3 methyltransferase modulators. Collectively, these small-molecule modulators proteins regulation potentially accelerate discovery.

Language: Английский

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Effects of DNA, RNA, and Protein Methylation on the Regulation of Ferroptosis

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(11), P. 3558 - 3575

Published: Jan. 1, 2023

Ferroptosis is a form of programmed cell death characterized by elevated intracellular ferrous ion levels and increased lipid peroxidation.Since its discovery characterization in 2012, considerable progress has been made understanding the regulatory mechanisms pathophysiological functions ferroptosis.Recent findings suggest that numerous organ injuries (e.g., ischemia/reperfusion injury) degenerative pathologies aortic dissection neurodegenerative disease) are driven ferroptosis.Conversely, insufficient ferroptosis linked to tumorigenesis.Furthermore, recent study revealed effect on hematopoietic stem cells under physiological conditions.The identified date include mainly iron metabolism, such as transport ferritinophagy, redox systems, glutathione peroxidase 4 (GPX4)-glutathione (GSH), ferroptosis-suppressor-protein 1 (FSP1)-CoQ10, FSP1-vitamin K (VK), dihydroorotate dehydrogenase (DHODH)-CoQ, GTP cyclohydrolase (GCH1)-tetrahydrobiopterin (BH4).Recently, an increasing number studies have demonstrated important role played epigenetic mechanisms, especially DNA, RNA, protein methylation, ferroptosis.In this review, we provide critical analysis molecular networks date, with focus methylation.Furthermore, discuss some debated unanswered questions should be foci future research field.

Language: Английский

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ALKBH5 decreases SLC7A11 expression by erasing m6A modification and promotes the ferroptosis of colorectal cancer cells

Clinical & Translational Oncology, Journal Year: 2023, Volume and Issue: 25(7), P. 2265 - 2276

Published: Feb. 23, 2023

Language: Английский

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