EBNA2 mediates lipid metabolism and tumorigenesis through activation of ATF4 pathway.
Jia Feng, Ping Zhang, Paul Yao

и другие.

PubMed, Год журнала: 2023, Номер 13(4), С. 1363 - 1376

Опубликована: Янв. 1, 2023

Epstein-Barr virus (EBV) can infect the majority of human population with no obvious symptoms and is associated tumor development, although mechanism still largely unknown. In this study, we investigated role underlying EBV nuclear antigen 2 (EBNA2) in tumorigenesis. We found that infection EBNA2 B lymphocytes (HBL) upregulated expression activating transcription factor 4 (ATF4). Furthermore, used gene or knockdown approach to demonstrate effect on redox balance, mitochondrial function, lipid metabolism, cell proliferation both HBL EBV-transformed lymphocyte line (LCL). More importantly, applied vivo xenograft mouse model explore contribution ATF4 growth survival. Mechanistically, revealed exposure caused persistent via EBNA2-mediated epigenetic changes, which increased binding ability upstream stimulating 1 (USF1) promoter. activation cells modulated metabolism-related genes potentiated fatty acid oxidation lipogenesis. Conversely, either LCL suppressed balance as well inhibited proliferation. consistent these findings from vitro an confirmed SREBP1, ChREBP, FAS, prolonged animal Collectively, study demonstrates mediates tumorigenesis through modulation metabolism; therefore, our provide a novel avenue for clinical treatment EBV-mediated cancer.

Язык: Английский

RNA splicing: novel star in pulmonary diseases with a treatment perspective DOI Creative Commons

Zhihui Niu,

Bingqian Xu, Xing Li

и другие.

Acta Pharmaceutica Sinica B, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
Relationship between arginine methylation and vascular calcification DOI
Chen Chen, Yuanyuan Ding, Qun Huang

и другие.

Cellular Signalling, Год журнала: 2024, Номер 119, С. 111189 - 111189

Опубликована: Апрель 25, 2024

Язык: Английский

Процитировано

3
Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions DOI Creative Commons
Pu Zhang, Lindsey T. Brinton, Mehdi Gharghabi

и другие.

Science Advances, Год журнала: 2022, Номер 8(37)

Опубликована: Сен. 16, 2022

Using a genome-wide CRISPR screen, we identified CDK9 , DHODH and PRMT5 as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 ( FLT3 )–internal tandem duplication (ITD) acute myeloid leukemia (AML) genetically pharmacologically validated their roles sensitivity. The presence of -ITD is associated an increase anaerobic glycolysis, rendering cells highly sensitive to inhibition glycolysis. Supportive this, our data show the enrichment single guide RNAs targeting 28 glycolysis-related genes upon treatment, suggesting that switching from glycolysis oxidative phosphorylation (OXPHOS) may represent metabolic adaption AML resistance. CDK9i/FLT3i, DHODHi/FLT3i, PRMT5i/FLT3i pairs mechanistically converge on OXPHOS purine biosynthesis blockade, implying functions these three and/or proteins attractive strategies sensitize treatment. Our findings provide basis for maximizing therapeutic impact inhibitors rationale clinical trial novel combinations.

Язык: Английский

Процитировано

13
Role of PRMT1 and PRMT5 in Breast Cancer DOI Open Access
Sébastien Martinez, Stéphanie Sentis, Coralie Poulard

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(16), С. 8854 - 8854

Опубликована: Авг. 14, 2024

Breast cancer is the most common diagnosed in women worldwide. Early-stage breast curable ~70–80% of patients, while advanced metastatic considered incurable with current therapies. a highly heterogeneous disease categorized into three main subtypes based on key markers orientating specific treatment strategies for each subtype. The complexity carcinogenesis often associated epigenetic modification regulating different signaling pathways, involved tumor initiation and progression, particularly by methylation arginine residues. Protein methyltransferases (PRMT1-9) have emerged, through their ability to methylate histones non-histone substrates, as essential regulators cancers. Here, we present an updated overview mechanisms which PRMT1 PRMT5, two major members PRMT family, control important pathways impacting tumorigenesis, highlighting them putative therapeutic targets.

Язык: Английский

Процитировано

2
Targeting the integrated stress response in hematologic malignancies DOI Creative Commons

Gus O. Nwosu,

Jason A. Powell, Stuart M. Pitson

и другие.

Experimental Hematology and Oncology, Год журнала: 2022, Номер 11(1)

Опубликована: Ноя. 8, 2022

Abstract While numerous targeted therapies have been recently adopted to improve the treatment of hematologic malignancies, acquired or intrinsic resistance poses a significant obstacle their efficacy. Thus, there is increasing need identify novel, targetable pathways further therapy for these diseases. The integrated stress response signaling pathway activated in cancer cells both dysregulated growth and metabolism, also following exposure many that appears one such improved In this review, we discuss role biology its critical involvement mechanism action therapies, as target pharmacologic modulation novel strategy malignancies.

Язык: Английский

Процитировано

10
Hydrogen peroxide activates APE1/Ref-1 via NF-κB and Parkin: a role in liver cancer resistance to oxidative stress DOI
Ferbian Milas Siswanto,

Kenta Okukawa,

Akiyoshi Tamura

и другие.

Free Radical Research, Год журнала: 2023, Номер 57(3), С. 223 - 238

Опубликована: Март 4, 2023

Cancer cells exhibit an altered redox balance and aberrant signaling due to genetic, metabolic, microenvironment-associated reprogramming. Persistently elevated levels of reactive oxygen species (ROS) contribute many aspects tumor development progression. Emerging studies demonstrated the vital role apurinic/apyrimidinic endonuclease 1 or reduction/oxidation (redox) factor 1(APE1/Ref-1) in oxidative stress response survival cancer cells. APE1/Ref-1 is a multifunctional enzyme involved DNA damage functions as regulator transcription factors. We herein that basal hydrogen peroxide (H2O2) expression were markedly higher cell lines than non-cancerous Elevated associated with shorter liver patients. Mechanistically, we showed H2O2 activated nuclear factor-κB (NF-κB). RelA/p65 inhibited E3 ubiquitin ligase Parkin, possibly by interfering ATF4 activity. Parkin was responsible for ubiquitination proteasomal degradation APE1/Ref-1; therefore, H2O2-induced suppression increased levels. The probability lower patients low high RelA Additionally, negatively positively correlated levels, respectively, TCGA cohort. concluded increases via NF-κB pathways are critical under stress. present results show potential NF-κB-Parkin-APE1/Ref-1 axis prognostic therapeutic strategy eradicate cancer.

Язык: Английский

Процитировано

5
High expression of miR-107 and miR-17 predicts poor prognosis and guides treatment selection in acute myeloid leukemia DOI Open Access
Yue Liu, Yang Cao, Xiaojun Yang

и другие.

Translational Cancer Research, Год журнала: 2023, Номер 12(4), С. 913 - 927

Опубликована: Март 20, 2023

The prognostic significance of miR-107 and miR-17 in patients with acute myeloid leukemia (AML) remains unclear.A total 173 de novo AML from the Cancer Genome Atlas database were enrolled this study further divided into a chemotherapy group (98 cases) an allogeneic hematopoietic stem cell transplantation (allo-HSCT) (75 according to their therapy regimen.In cohort, high or expression was associated poorer overall survival (OS) event-free (EFS). On other hand, there no significant differences OS EFS between high- low-expression subgroups allo-HSCT group. Next, we stratified number groups median levels miR-17. In group, treated had longer than those chemotherapy. low observed two subgroups. When clustered three (both miR-17, either both miR-17), worst entire among Cox regression confirmed concurrence might act as independent factor for Bioinformatics analysis showed differentially expressed genes (DEGs) mainly enriched multiple metabolic processes.The combination provides should be considered clinical selection optimal treatment regimen when deciding allo-HSCT.

Язык: Английский

Процитировано

4
PRMT5 is required for full-lengthHTTexpression by repressing multiple proximal intronic polyadenylation sites DOI Creative Commons
Mona Alqazzaz, Felipe E. Ciamponi, Jolene Caifeng Ho

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 14, 2024

Abstract Expansion of the CAG trinucleotide repeat tract in exon 1 Huntingtin ( HTT ) gene above a threshold ∼36 repeats causes Huntington’s disease (HD) through expression polyglutamine-expanded form protein. This mutation triggers wide-ranging cellular and biochemical pathologies leading to cognitive, motor, psychiatric symptoms HD patients. As accurate splicing is required produce full-length protein ∼348 kDa, targeting with small molecule drugs compelling approach lower levels treat HD, splice modulators are being tested clinic. Here, we identify PRMT5 as novel regulator mRNA alternative polyadenylation. inhibition disrupts introns 9 10, activation multiple proximal intronic polyadenylation sites within these promoting premature termination, cleavage (PCPA) mRNA, thus lowering total levels. We also detected increasing truncated, intron-containing transcripts across series neuronal differentiation samples which correlated expression. Notably, glioblastoma (GBM) stem cells potently induced differentiation. posit that PRMT5-mediated regulation polyadenylation, termination modulates plays an important role during embryonic development

Язык: Английский

Процитировано

0
Protein arginine methyltransferase 5 in osteoblasts promotes the healing of extraction sockets DOI
Jie Yang, Shurong Yang, Xuejun Ge

и другие.

Oral Diseases, Год журнала: 2024, Номер 30(6), С. 3951 - 3961

Опубликована: Янв. 31, 2024

Abstract Objectives To explore the effect of protein arginine methyltransferase 5 (PRMT5) on tooth extraction sockets healing, we established an model in osteoblast‐conditional Prmt5 knockout mice. The results provided clues for promoting healing clinical settings. Materials and Methods Maxillary first molars were extracted from 6 to 8‐week‐old mice establish fossa model. Microcomputed tomography (Micro‐CT), histology, immunostaining assays performed samples harvested at 3‐, 7‐, 14‐day post‐extraction. ‐silenced cell lines employed regulatory mechanisms underlying osteigenic differentiation. Results PRMT5 expression was higher early stage socket healing. Micro‐CT analysis showed that percentage new bone lower OC‐Cre; fl/fl than control group, consistent with Masson staining. We found that, deficiency delayed osteogenesis during which might be achieved through decrease H4R3me2s Sp7 promoter region. Conclusion osteoblasts may promote differentiation by regulating Sp 7 participate sockets.

Язык: Английский

Процитировано

0
LINC00894 Regulates Cerebral Ischemia/Reperfusion Injury by Stabilizing EIF5 and Facilitating ATF4-Mediated Induction of FGF21 and ACOD1 Expression DOI Creative Commons
Yifei Chen, Hengxiang Cui,

Zhuanzhuan Han

и другие.

Neurochemical Research, Год журнала: 2024, Номер 49(10), С. 2910 - 2925

Опубликована: Июль 26, 2024

Abstract The non-coding RNA LINC00894 modulates tumor proliferation and drug resistance. However, its role in brain is still unclear. Using RNA-pull down combined with mass spectrometry binding protein immunoprecipitation, EIF5 was identified to interact LINC00894. Furthermore, knockdown decreased expression, whereas overexpression increased expression SH-SY5Y BE(2)-M17 (M17) neuroblastoma cells. Additionally, affected the ubiquitination modification of EIF5. Adeno-associated virus (AAV) mediated inhibited activated Caspase-3, while level rats mice subjected transient middle cerebral artery occlusion reperfusion (MCAO/R). Meanwhile, number apoptotic cells them oxygen–glucose deprivation reoxygenation (OGD/R) vitro models. Further, revealed regulated ATF4 condition OGD/R normoxia. also glutamate-cysteine ligase catalytic subunit (GCLC) ATF4, downregulated glutathione (GSH), ratio GSH oxidized (GSH: GSSG) vitro. By using RNA-seq qRT-PCR immunoblot, we that fibroblast growth factor 21 (FGF21) aconitate decarboxylase 1 (ACOD1), as target genes were by MCAO/R model. Finally, transcriptionally FGF21 ACOD1 expression; ectopic or Caspase-3 Our results demonstrated ischemia injury stabilizing facilitating EIF5-ATF4-dependent induction ACOD1.

Язык: Английский

Процитировано

0