UBE2T/CDC42/CD276 signaling axis mediates brain metastasis of triple-negative breast cancer via lysosomal autophagy

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e010782 - e010782

Published: Feb. 1, 2025

Background Advanced triple-negative breast cancer (TNBC) is prone to brain metastasis (BrM). The precise molecular mechanism responsible for this phenomenon has not yet been completely established, so it vital comprehend the behind it. Methods protein chip analysis was conducted identify any abnormal UBE2T expression in TNBC, especially BrM. Here, we used public databases and bioinformatics as well clinical samples from different cohorts investigate interrelationship between UBE2T/CDC42/CD276. This predicted relationship then repeatedly validated using vivo vitro experimental methods. Additionally, multiple approaches were implemented, encompassing western blotting, Co-IP, GST pull-down, flow cytometry, mass spectrometry, immunofluorescence, immunohistochemistry, qRT-PCR reveal of UBE2T-mediated immune escape Results Our results indicate that expressed at elevated levels cancer, negatively linked patient prognosis, BrM TNBC. Data our TCGA a significant correlation immunosuppression. Mechanistically, directly interacts with CDC42, promoting its K48-linked polyubiquitination proteasomal degradation, thereby inhibiting CDC42 degrading CD276 via autophagy-lysosomal pathway, indirectly upregulating impairing CD8 + T cells function, ultimately mediating tumor Finally, animal also showed inhibition TNBC sensitivity checkpoint blockade inhibited Conclusions In conclusion, new whereby ubiquitination positively controls UBE2T/CDC42/CD276 axis upregulate cell impair leading

Language: Английский

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NSUN3 Aggravates Sepsis‐Associated Acute Kidney Injury by Stabilising TIFA mRNA Through m5C

Clinical and Experimental Pharmacology and Physiology, Journal Year: 2025, Volume and Issue: 52(4)

Published: Feb. 9, 2025

ABSTRACT Background Acute kidney injury (AKI) is a common complication of sepsis and also risk factor for progression chronic disease. NOP2/Sun RNA methyltransferase 3 (NSUN3) involved in the regulation progression. However, mechanism by which NSUN3 regulates sepsis‐associated AKI (SA‐AKI) remains unclear. Methods SA‐AKI mouse model lipopolysaccharide (LPS)‐induced HK‐2 cells were constructed. Haematoxylin–eosin staining, quantitative polymerase chain reaction (qPCR), western blotting, cell counting kit 8, flow cytometry, 2′,7′‐dichlorofluorescein diacetate, enzyme‐linked immunosorbent assay, methylation immunoprecipitation‐qPCR, actinomycin D TdT‐mediated dUTP Nick‐End Labelling staining assays utilised to explore expression related models. Results The tumour necrosis receptor‐associated (TRAF)‐interacting protein with forkhead‐associated domain (TIFA) was upregulated mice LPS‐induced cells. Knockdown inhibited Mechanically, increased TIFA mRNA stability its through m5C modification. Moreover, knockdown found alleviate reducing expression. Conclusion aggravates stabilising m5C, indicating that may be biomarker SA‐AKI.

Language: Английский

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Epitranscriptomics in the Glioma Context: A Brief Overview

Cancers, Journal Year: 2025, Volume and Issue: 17(4), P. 578 - 578

Published: Feb. 8, 2025

Epitranscriptomics, the study of chemical modifications in RNA, has emerged as a crucial field cellular regulation, adding another layer to established landscape DNA- and histone-based epigenetics. A wide range RNA modifications, including N6-methyladenosine, pseudouridine, inosine, have been identified across nearly all species, influencing essential processes such transcription, splicing, stability, translation. In context brain tumors, particularly gliomas, specific epitranscriptomic signatures reported play role tumorigenesis. Despite growing evidence, biological implications various remain poorly understood. This review offers an examination main interplay between modified unmodified molecules, how they could contribute glioma-like phenotypes, therapeutic impact targeting these mechanisms.

Language: Английский

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NSUN4 Facilitates the Activity of Oncogenic Protein CDC20 to Promote NSCLC Development by Mediating m5C Modification of CDC20 mRNA

Thoracic Cancer, Journal Year: 2025, Volume and Issue: 16(5)

Published: March 1, 2025

5-methylcytosine (m5C) methylation is the crucial posttranscriptional modification of RNA. NSUN4, a methyltransferase for m5C methylation, contributes to lung tumorigenesis. Here, we determined precise action NSUN4 on development non-small cell cancer (NSCLC). and CDC20 mRNA expression was detected by quantitative PCR. Western blot immunohistochemistry were used analysis protein expression. Cell growth, apoptosis, invasiveness, migratory ability, stemness potential evaluated colony formation, flow cytometry, transwell, sphere formation assays. The influence in analyzed using RNA immunoprecipitation (RIP) assay Actinomycin D (Act D) treatment. Subcutaneous xenograft studies performed analyze function vivo. In human NSCLC tumors lines, levels upregulated. inhibition diminished stemness, ability vitro, while increase had opposite effects. A positive association between observed samples. Mechanistically, enhanced stability through modification. depletion significantly counteracted NSUN4-driven phenotype alterations vitro. Additionally, impeded growth A549 subcutaneous xenografts Our findings identify pro-tumorigenic property NSUN4/CDC20 cascade NSCLC. Targeting novel may be promising way combating this deadly disease.

Language: Английский

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Exploring the impact of cuproptosis on prostate cancer prognosis via RNA methylation regulation based on single cell and bulk RNA sequencing data

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 1, 2025

Cuproptosis, along with RNA methylation regulators, has recently come to the fore as innovative mechanisms governing cell death, exerting profound impact on onset and progression of multiple cancers. Nonetheless, prognostic implications underlying regulatory them associated prostate cancer (PCa) remain be thoroughly investigated. Genomic clinical data for PCa from The Cancer Genome Atlas datasets were analyzed identify a model through univariate Least Absolute Shrinkage Selection Operator Cox regression analyses that validated utilizing external datasets. We used receiver operating characteristic curves C-index evaluate accuracy our model. In conjunction this, we conducted single-cell sequencing (scRNA-seq) investigate degree immune infiltration, well assess patients' responses diverse chemotherapy agents. Especially, qPCR assay was utilized unveil expression signature genes in PCa. meticulously selected six Cuproptosis-Associated Methylation Regulators (CARMRs) establish risk prognosis model, which further verified obtain enhanced predictive capacity validation cohorts. Insights infiltration scRNA-seq have elucidated characteristics PCa, highlighted immunosuppressive role T cells response. Additionally, drug susceptibility analysis demonstrated patients low-risk category derived better benefit bicalutamide treatment, whereas those high-risk group exhibited favor response adriamycin docetaxel treatments. immunohistochemistry (IHC) staining assays also reveal dramatically altered pattern TRDMT1 ALYREF tissues. general, established involving CARMRs can predict recurrence identified possible affecting progression, thereby promoting research this field.

Language: Английский

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ALYREF recruits ELAVL1 to promote colorectal tumorigenesis via facilitating RNA m5C recognition and nuclear export

npj Precision Oncology, Journal Year: 2024, Volume and Issue: 8(1)

Published: Oct. 25, 2024

ALYREF can recognize 5-methylcytosine (m5C) decoration throughout RNAs to regulate RNA metabolism. However, its implications in cancer and precise regulatory mechanisms remain largely elusive. Here, we demonstrated that supported colorectal (CRC) growth migration. Integrated analysis of ALYREF-RIP-Bis-seq transcriptome profiles identified ribosomal protein S6 kinase B2 (RPS6KB2) regulatory-associated mTOR (RPTOR) as ALYREF's possible downstream effectors. Mechanistically, formed a complex with ELAV like binding 1 (ELAVL1) cooperatively promote m5C recognition nuclear export the two mRNAs. Moreover, was highly expressed tumor tissues CRC patients, which predicted their poor prognosis. E2F transcription factor 6 (E2F6)-mediated transactivation gave molecular insight into overexpression. Collectively, recruits ELAVL1 collaboratively facilitate RPS6KB2 RPTOR transcripts for tumorigenesis, providing methylation promising therapeutic targets prognostic biomarkers CRC.

Language: Английский

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The diverse landscape of RNA modifications in cancer development and progression

Genes & Genomics, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 6, 2024

Language: Английский

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RNA Methyltransferase NSUN5 Promotes Esophageal Cancer via 5‐Methylcytosine Modification of METTL1

Molecular Carcinogenesis, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

Aberrant RNA modifications can drive carcinogenic transformation and tumor progression, with 5-methylcytosine (m5C) emerging as one of the predominant in eukaryotic cells. However, function molecular mechanisms m5C esophageal cancer (ESCA) remain insufficiently defined. Here we report that methyltransferase NOP2/Sun domain family member 5 (NSUN5) is significantly upregulated ESCA tumors shows promising diagnostic potential. Functionally, knockdown NSUN5 impairs proliferation capacity cells arrests cell cycle at G0/G1 phase, while enforced expression accelerates progression. In vivo, deficiency reduces growth a cell-based xenograft mouse model. Mechanistically, correlates oncogenic like 1 (METTL1), positively regulating its expression; binds directly to METTL1 transcript, facilitating modification Additionally, overexpression effectively counteracts tumor-suppressive effects resulting from ablation both vitro vivo settings. A comprehensive pan-cancer analysis further underscores NSUN5's essential role digestive system tumors, downregulation notably inhibiting gastric colon growth. These findings provide new insights into epigenetic regulation propose NSUN5/METTL1 axis therapeutic target for this malignancy.

Language: Английский

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Significant roles of RNA 5-methylcytosine methylation in cancer

Cellular Signalling, Journal Year: 2024, Volume and Issue: 126, P. 111529 - 111529

Published: Nov. 28, 2024

Language: Английский

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