METTL3-mediated m6A modification of SLC7A11 enhances nasopharyngeal carcinoma radioresistance by inhibiting ferroptosis

International Journal of Biological Sciences, Год журнала: 2025, Номер 21(4), С. 1837 - 1851

Опубликована: Фев. 10, 2025

Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC); nonetheless, radioresistance remains leading cause of localized recurrence. Our study demonstrates a significant increase in N6-methyladenosine (m6A) methylase METTL3 NPC and other tumors. Mechanistically, acts as an m6A methylase, enhancing modification solute carrier family 7 member 11 (SLC7A11) transcript, which increases its stability expression, thereby inhibiting radiation-induced ferroptosis ultimately inducing NPC. Furthermore, silencing SLC7A11 or employing inducer Erastin negated promoting effect on cell radioresistance. These findings suggest that could be novel therapeutic target overcoming radiotherapy resistance

Язык: Английский

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Super enhancer lncRNAs: a novel hallmark in cancer

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Апрель 2, 2024

Abstract Super enhancers (SEs) consist of clusters enhancers, harboring an unusually high density transcription factors, mediator coactivators and epigenetic modifications. SEs play a crucial role in the maintenance cancer cell identity promoting oncogenic transcription. enhancer lncRNAs (SE-lncRNAs) refer to either transcript from locus or interact with SEs, whose transcriptional activity is highly dependent on SEs. Moreover, these SE-lncRNAs can their associated regions cis modulate expression oncogenes key signal pathways cancers. Inhibition would be promising therapy for cancer. In this review, we summarize research different kinds cancers so far decode mechanism carcinogenesis provide novel ideas therapy.

Язык: Английский

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RNA N6-Methyladenosine Modification in DNA Damage Response and Cancer Radiotherapy

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2597 - 2597

Опубликована: Фев. 23, 2024

The N6-methyladenosine (M6A) modification is the most common internal chemical of RNA molecules in eukaryotes. This can affect mRNA metabolism, regulate transcription, nuclear export, splicing, degradation, and translation, significantly impact various aspects physiology pathobiology. Radiotherapy method tumor treatment. Different intrinsic cellular mechanisms response cells to ionizing radiation (IR) effectiveness cancer radiotherapy. In this review, we summarize discuss recent advances understanding roles M6A methylation responses radiation-induced DNA damage determining outcomes Insights into biology may facilitate improvement therapeutic strategies for radiotherapy radioprotection normal tissues.

Язык: Английский

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METTL14 promotes lipid metabolism reprogramming and sustains nasopharyngeal carcinoma progression via enhancing m⁶A modification of ANKRD22 mRNA

Clinical and Translational Medicine, Год журнала: 2024, Номер 14(7)

Опубликована: Июль 1, 2024

Abstract Background N 6 ‐methyladenosine (m A) modification is essential for modulating RNA processing as well expression, particularly in the context of malignant tumour progression. However, exploration m A nasopharyngeal carcinoma (NPC) remains very limited. Methods levels were analysed NPC using dot blot assay. The expression level methyltransferase‐like 14 (METTL14) within tissues was from public databases RT‐qPCR and immunohistochemistry. influences on METTL14 proliferation metastasis explored via vitro vivo functional assays. Targeted genes screened gene profiling microarray data. Actinomycin D treatment polysome analysis used to detect half‐life translational efficiency ANKRD22. Flow cytometry, immunofluorescence immunoprecipitation validate role ANKRD22 lipid metabolism cells. ChIP‐qPCR H3K27AC signalling near promoters METTL14, GINS3, POLE2, PLEK2 FERMT1 genes. Results We revealed NPC, correlating with poor patient prognosis. In assays indicated actively promoted cells metastasis. catalysed messenger ribonucleic acid (mRNA), recognized by reader IGF2BP2, leading increased mRNA stability higher efficiency. Moreover, ANKRD22, a metabolism‐related protein mitochondria, interacted SLC25A1 enhance citrate transport, elevating intracellular acetyl‐CoA content. This dual impact reprogramming cellular synthesis while upregulating associated cell cycle (GINS3 POLE2) cytoskeleton (PLEK2 FERMT1) through heightened epigenetic histone acetylation nucleus. Intriguingly, our findings highlighted elevated ANKRD22‐mediated H3 lysine 27 (H3K27AC) signals promoter, which contributes positive feedback loop perpetuating progression NPC. Conclusions identified METTL14‐ANKRD22‐SLC25A1 axis emerges promising therapeutic target also these molecules may serve novel diagnostic biomarkers.

Язык: Английский

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LncRNA HOTAIRM1 promotes radioresistance in nasopharyngeal carcinoma by modulating FTO acetylation-dependent alternative splicing of CD44

Neoplasia, Год журнала: 2024, Номер 56, С. 101034 - 101034

Опубликована: Авг. 10, 2024

Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC); however, almost 20% of experience failure due to radioresistance. Therefore, understanding mechanisms radioresistance imperative. HOTAIRM1 deregulated in various human cancers, yet its role NPC are largely unclear.

Язык: Английский

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The interplay between RNA m⁶A modification and radiation biology of cancerous and non-cancerous tissues: a narrative review

Cancer Biology and Medicine, Год журнала: 2025, Номер 21(12), С. 1120 - 1140

Опубликована: Янв. 17, 2025

The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous non-cancerous tissues. Radiation therapy (RT) induces oncological responses, from molecular to phenotypic alterations, while simultaneously exerting toxic healthy tissue. N6-methyladenosine (m6A), a prevalent modification coding non-coding RNAs, is key epigenetic mark established by set of evolutionarily conserved enzymes. interplay between m6A radiobiology tissues merits in-depth investigation. This review summarizes roles induced ionizing ultraviolet (UV) radiation. It begins with an overview its detection methods, followed detailed examination how dynamically regulates sensitivity RT, injury response tissues, toxicological UV exposure. Notably, this underscores importance novel regulatory mechanisms their potential clinical applications identifying epigenetically modulated radiation-associated biomarkers for cancer estimation dosages. In conclusion, enzyme-mediated m6A-modification triggers alterations target gene expression affecting metabolism modified thus modulating progression radiosensitivity as well normal Several promising avenues future research are further discussed. highlights context biology. Targeting epi-transcriptomic molecules might potentially provide strategy enhancing mitigating radiation-induced

Язык: Английский

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A super-enhancer actuated by heterodimerization of a specific YAP1 isoform, YAP1-2α, with TAZ endows cancer stemness and drug resistance

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

ABSTRACT The acquisition of drug resistance poses a significant challenge for successful cancer treatment. Understanding the mechanisms by which evades action is crucial developing effective therapies. PARP inhibitors (PARPi) induce synthetic lethality in BRCA -deficient cells; however, these cells eventually develop PARPi resistance. Here, we demonstrate that prolonged exposure to or Cisplatin leads alterations YAP1 pre-mRNA splicing patterns, resulting selective upregulation minor isoform, YAP1-2α. Elevated YAP1-2α specifically heterodimerizes with TAZ, triggering liquid-liquid phase separation (LLPS). This process generates nuclear condensates activate super-enhancers containing YAP1-2α/TAZ heterodimer, TEAD, and BRD4. These (here referred as YAP1-2α/TAZ/TEAD super-enhancers) are also activated CD44(variant) high stem-like populations parental cells. In both PARPi-resistant cell populations, treatments disrupt abolish properties. Thus, activation reinforces stemness, confers adverse conditions, such those caused anticancer treatment, including Cisplatin. Our investigation reveals transcriptionally facilitate malignant grade Disrupting represents promising strategy hinder neoplastic progression prevent multidrug

Язык: Английский

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BRD4 inhibition sensitizes glioblastoma to radiotherapy by suppressing super-enhancer-driven COL1A1

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 19, 2025

Radiotherapy (RT) combined with chemotherapy is the standard treatment for newly diagnosed glioblastoma (GBM). However, limited RT efficacy and RT-related cancer resistance have spurred interest in radiosensitizing strategies of GBM. We aimed to explore synergistic BRD4 inhibitor I-BET151 combination GBM therapy. found upregulated after was correlated radiosensitivity. sensitized cells by inhibiting cell proliferation, inducing apoptosis, thus prolonging survival subcutaneous orthotopic murine GL261 mouse models. In vitro, suppressing increasing sustainable DNA damage. Mechanistically, integrated H3K27ac ChIP-seq RNA-seq analysis identified COL1A1 as a key BRD4-dependent super-enhancer (SE)-driven target post-RT, which also validated ChIP-qPCR. Moreover, RNAi-mediated silencing reduced increased enhanced RT-induced damage, underscoring its pivotal role BRD4-mediated radioresistance. inhibition may enhance radiosensitivity infiltration macrophage, neutrophil enhancing CD8 + T accumulation. conclusion, contributes ECM remodeling radioresistance SE-driven COL1A1-dependent manner. Thus, targeting rationale strategy augment treatment.

Язык: Английский

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The emerging significance of the METTL family as m6A-modified RNA methyltransferases in head and neck cancer

Cellular Signalling, Год журнала: 2025, Номер unknown, С. 111798 - 111798

Опубликована: Апрель 1, 2025

Язык: Английский

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Interactions between long non-coding RNAs and m6 A modification in cancer

Discover Oncology, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 20, 2025

Long non-coding RNAs (lncRNAs) are a class of transcripts exceeding 200 nucleotides (nt) in length, which broadly implicated broad spectrum physiological and pathological processes, including allelic imprinting, genome packaging, chromatin remodeling, transcriptional activation disruption, as well the occurrence progression oncogenesis. N6-methyladenosine (m6 A) methylation stands most prevalent RNA modification, affecting multiple facets biology such stability, splicing, transport, translation, degradation, tertiary structure. Aberrant m6 A modifications intimately cancer progression. In recent years, there has been growing number studies illuminating dynamic interplay between lncRNAs modifications, revealing that can modulate activity regulators, while not only affects structural integrity but also translational efficiency stability lncRNAs. Together, interactions significantly impact downstream oncogenes, suppressor genes, cellular metabolism, epithelial-mesenchymal transition, angiogenesis, drug DNA homology repair, epigenetics, subsequently influencing tumorigenesis, metastasis, resistance. This article endeavors to clarify functions mechanisms interaction provide promising insights for diagnosis therapeutic strategies.

Язык: Английский

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