Trichostatin A augments cell migration and epithelial-mesenchymal transition in esophageal squamous cell carcinoma through BRD4/c-Myc endoplasmic reticulum-stress pathway DOI

Yanmin Chen,

Wenqian Yang, Yingying Fan

et al.

World Journal of Gastroenterology, Journal Year: 2025, Volume and Issue: 31(11)

Published: March 12, 2025

BACKGROUND The causes of death in patients with advanced esophageal cancer are multifactorial, tumor metastasis being one the important factors. Histone acetylation promotes migration squamous cell carcinoma (ESCC) cells, while histone deacetylase inhibitor (HDACi) shows complex effects on functions. AIM To comprehensively elucidate impact and molecular mechanisms trichostatin A (TSA), an HDACi, ESCC through bromodomain-containing protein (BRD4)/cellular myelocytomatosis oncogene (c-Myc)/endoplasmic reticulum (ER)-stress. METHODS TSA lines Eca109 EC9706 were evaluated using Transwell assays, small interfering transfection pathway-specific inhibitors to underlying mechanisms. mRNA levels involved examined by quantitative real-time polymerase chain reaction. Protein acetylated histones H3 (acH3) H4, BRD4, c-Myc, as well markers ER stress epithelial-mesenchymal transition (EMT), analyzed western blot. Additionally, this method was also used examine acH3 tissues adjacent tissues. Patient outcomes subsequently tracked identify prognostic indicators Log-Rank tests Cox multivariate analysis. RESULTS promoted cells stimulating EMT process. TSA-mediated facilitated recruitment a protein, triggering expression c-Myc. This cascade induced enhanced cells. further mechanism, we employed various interventions including 4-phenylbutyric acid, knockdown c-Myc BRD4 expression, utilization carboxylic acid 1. Mechanistically, these studies revealed that which turn triggered sequential activation EMT, thereby promoting specimens from 43 ESCC, both paired Statistical analysis unveiled negative correlation between level long-term prognosis ESCC. CONCLUSION BRD4/c-Myc/ER pathway. Moreover, elevated correlated poor prognosis. These findings enhance our understanding HDACi therapy.

Language: Английский

RNA modification: mechanisms and therapeutic targets DOI Creative Commons
Lei Qiu, Jing Qian, Yanbo Li

et al.

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Aug. 24, 2023

Abstract RNA modifications are dynamic and reversible chemical on substrate that regulated by specific modifying enzymes. They play important roles in the regulation of many biological processes various diseases, such as development cancer other diseases. With help advanced sequencing technologies, role has caught increasing attention human diseases scientific research. In this review, we briefly summarized basic mechanisms several common modifications, including m6A, m5C, m1A, m7G, Ψ, A-to-I editing ac4C. Importantly, discussed their potential functions cancer, neurological disorders, cardiovascular metabolic genetic developmental well immune disorders. Through “writing-erasing-reading” mechanisms, regulate stability, translation, localization pivotal disease-related mRNAs to manipulate disease development. Moreover, also highlighted review all currently available RNA-modifier-targeting small molecular inhibitors or activators, most which designed against m6A-related enzymes, METTL3, FTO ALKBH5. This provides clues for clinical therapy future study directions modification field. More in-depth studies further activators needed a thorough understanding epitranscriptomics diagnosis, treatment, prognosis

Language: Английский

Citations

68
Emerging role of RNA acetylation modification ac4C in diseases: Current advances and future challenges DOI
Jie Luo, Jingsong Cao, Cong Chen

et al.

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 213, P. 115628 - 115628

Published: May 27, 2023

Language: Английский

Citations

34
Lenvatinib in hepatocellular carcinoma: Resistance mechanisms and strategies for improved efficacy DOI
Y. Qin, Shisong Han, Yahan Yu

et al.

Liver International, Journal Year: 2024, Volume and Issue: 44(8), P. 1808 - 1831

Published: May 3, 2024

Hepatocellular carcinoma (HCC), one of the most prevalent and destructive causes cancer-related deaths worldwide, approximately 70% patients with HCC exhibit advanced disease at diagnosis, limiting potential for radical treatment. For such patients, lenvatinib, a long-awaited alternative to sorafenib first-line targeted therapy, has become key Unfortunately, despite some progress, prognosis remains poor because drug resistance development. However, molecular mechanisms underlying lenvatinib ways relief in are largely unknown lack systematic summary; thus, this review not only aims explore factors contributing HCC, but more importantly, summary methods conquer or mitigate resistance. The results suggest that abnormal activation pathways, transport, epigenetics, tumour microenvironment, cancer stem cells, regulated cell death, epithelial-mesenchymal transition, other involved development subsequent progression. To improve therapeutic outcomes inhibiting acquired resistance, combined therapies, nano-delivery carriers may be possible approaches.

Language: Английский

Citations

14
Bioinformatics integration reveals key genes associated with mitophagy in myocardial ischemia-reperfusion injury DOI Creative Commons
Zhian Chen, Tianying Liu, Hao Yuan

et al.

BMC Cardiovascular Disorders, Journal Year: 2024, Volume and Issue: 24(1)

Published: March 27, 2024

Background Myocardial ischemia is a prevalent cardiovascular disorder associated with significant morbidity and mortality. While prompt restoration of blood flow essential for improving patient outcomes, the subsequent reperfusion process can result in myocardial ischemia–reperfusion injury (MIRI). Mitophagy, specialized autophagic mechanism, has consistently been implicated various disorders. However, specific connection between mitophagy remains elusive. This study aims to elucidate validate central mitophagy-related genes MIRI through comprehensive bioinformatics analysis. Methods We acquired microarray expression profile dataset (GSE108940) from Gene Expression Omnibus (GEO) identified differentially expressed (DEGs) using GEO2R. Subsequently, these DEGs were cross-referenced database, differential nucleotide sequence analysis was performed enrichment Protein–protein interaction (PPI) network employed identify hub genes, followed by clustering cytoHubba MCODE within Cytoscape software. set (GSEA) conducted on genes. Additionally, Western blotting, immunofluorescence, quantitative polymerase chain reaction (qPCR) analyses patterns pivotal rat model H9C2 cardiomyocytes. Results A total 2719 61 mitophagy-DEGs identified, construction PPI network. HSP90AA1, RPS27A, EEF2, EIF4A1, EIF2S1, HIF-1α, BNIP3 emerged as seven Functional HIF-1α yielded score 9.647, determined (MCODE). In our model, blot immunofluorescence confirmed elevation BNIP3, accompanied notable increase ratio LC3II LC3I. qPCR upregulation LC3 mRNA group. Activation HIF-1α/BNIP3 pathway mediates regulation degree thereby effectively reducing apoptosis Conclusions among that may play role MIRI, suggesting correlation pathogenesis MIRI. The findings highlight potential importance provide valuable insights into underlying mechanisms therapeutic targets further exploration future studies.

Language: Английский

Citations

9
Endoplasmic reticulum stress-related super enhancer promotes epithelial-mesenchymal transformation in hepatocellular carcinoma through CREB5 mediated activation of TNC DOI Creative Commons
Anqi Wang,

Sitong Yan,

Jiatao Liu

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 6, 2025

Abstract Super-enhancers (SEs) are associated with key genes that control cellular state and cell identity. Endoplasmic reticulum stress (ERS) regulates epithelial-mesenchymal transformation (EMT). However, whether SEs involved in ERS-related activation of EMT hepatocellular carcinoma (HCC) is unknown. In this study, we identified 17 by comparing ERS-HCC cells untreated using ChIP-seq RNA-seq. CRISPR-Cas9 RT-qPCR CAMP responsive element binding protein 5 (CREB5) as a target SE. Analyses TCGA datasets tissue arrays showed CREB5 mRNA expression levels were higher liver cancer tissues than paired normal tissues. addition, overexpression was poor prognosis an aggressive phenotype patients HCC. We also found ERS enhanced the CREB5, upregulation significantly increased proliferation, migration, invasion, promoted EMT, but inhibited apoptosis. More importantly, several markers modulating CREB5. Mechanistically, upregulates transcription tenascin-C (TNC) directly to its promoter region, thereby promoting cells. summary, our findings suggest promotes via SE-mediated CREB5/TNC pathway. This result provides new direction for uncovering how foundation preventing progression

Language: Английский

Citations

1
Emerging roles of RNA ac4C modification and NAT10 in mammalian development and human diseases DOI
Yigan Zhang,

Yumei Lei,

Yanbin Dong

et al.

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 253, P. 108576 - 108576

Published: Dec. 7, 2023

Language: Английский

Citations

22
Targeting N4‐acetylcytidine suppresses hepatocellular carcinoma progression by repressing eEF2‐mediated HMGB2 mRNA translation DOI Creative Commons
Hailing Liu, Lei Xu, Shiwei Yue

et al.

Cancer Communications, Journal Year: 2024, Volume and Issue: 44(9), P. 1018 - 1041

Published: July 19, 2024

Abstract Background N4‐acetylcytidine (ac4C) represents a novel messenger RNA (mRNA) modification, and its associated acetyltransferase N‐acetyltransferase 10 (NAT10) plays crucial role in the initiation progression of tumors by regulating mRNA functionality. However, hepatocellular carcinoma (HCC) development prognosis is largely unknown. This study aimed to elucidate NAT10‐mediated ac4C HCC provide promising therapeutic approach. Methods The levels were evaluated dot blot ultra‐performance liquid chromatography‐tandem mass spectrometry with harvested tissues. expression NAT10 was investigated using quantitative real‐time polymerase chain reaction, western blotting, immunohistochemical staining across 91 cohorts patients. To explore underlying mechanisms NAT10‐ac4C HCC, we employed comprehensive approach integrating acetylated immunoprecipitation sequencing, sequencing ribosome profiling analyses, along immunoprecipitation, pull‐down, spectrometry, site‐specific mutation analyses. drug affinity responsive targets stability, cellular thermal shift assay, surface plasmon resonance assays performed assess specific binding Panobinostat. Furthermore, efficacy targeting for treatment elucidated through vitro experiments cells vivo mouse models. Results Our investigation revealed significant increase both level HCC. Notably, elevated poor outcomes Functionally, silencing suppressed proliferation metastasis vivo. Mechanistically, stimulates modification within coding sequence (CDS) high mobility group protein B2 (HMGB2), which subsequently enhances HMGB2 translation facilitating eukaryotic elongation factor 2 (eEF2) sites on mRNA's CDS. Additionally, high‐throughput compound library screening Panobinostat as potent inhibitor modification. inhibition significantly attenuated growth Conclusions identified oncogenic epi‐transcriptome axis involving NAT10‐ac4C/eEF2‐HMGB2, pivotal metastasis. validates potential this treatment.

Language: Английский

Citations

8
NAT10 promotes synovial aggression by increasing the stability and translation of N4-acetylated PTX3 mRNA in rheumatoid arthritis DOI
Di Liu, Yu Kuang,

Simin Chen

et al.

Annals of the Rheumatic Diseases, Journal Year: 2024, Volume and Issue: unknown, P. ard - 225343

Published: May 8, 2024

Recent studies indicate that N-acetyltransferase 10 (NAT10)-mediated ac4C modification plays unique roles in tumour metastasis and immune infiltration. This study aimed to uncover the role of NAT10-mediated fibroblast-like synoviocytes (FLSs) functions synovial cell infiltration rheumatoid arthritis (RA).

Language: Английский

Citations

7
The emerging roles of ac4C acetylation “writer” NAT10 in tumorigenesis: A comprehensive review DOI
Leisheng Wang, Tao Yue, Jingbo Zhai

et al.

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 254, P. 127789 - 127789

Published: Nov. 4, 2023

Language: Английский

Citations

16
Dissecting the oncogenic properties of essential RNA-modifying enzymes: a focus on NAT10 DOI
Mahmood Hassan Dalhat, Sharath Narayan,

Hannah Serio

et al.

Oncogene, Journal Year: 2024, Volume and Issue: 43(15), P. 1077 - 1086

Published: Feb. 26, 2024

Language: Английский

Citations

5