TISSUE & CELL
·
2022
·
IF 2.586
Yanyan Pan,Min Wei,Ting Gong
Ultrasound-targeted microbubble destruction (UTMD) is a new gene therapy method that uses ultrasound and microbubbles carrying target genes to achieve gene transfection. However, whether UTMD-mediated ANLN silencing transfection helps to restrain the growth of cervical cancer (CC) is obscure. ANLN level in tumor tissues, adjacent tissues, and cells was tested using the database, qRT-PCR, and western blot . The optimal concentration of SF6 was determined by MTT assay . Mechanical index (MI) was selected by flow cytometry. After transfection with liposome or UTMD-mediated liposome, cell function experiments, qRT-PCR, and western blot were employed to assess CC cell biological behaviors and EZH2 level. Epithelial-mesenchymal transition (EMT)-related marker and apoptosis-related marker expressions were examined utilizing qRT-PCR and western blot. 10% SF6 and MI of 0.28 were selected for subsequent tests. ANLN was highly expressed in CC and cells. The transfection efficiency of the UTMD-siANLN group was higher than that of the L -siANLN group. Moreover, the repression of UTMD-siANLN on CC cell malignant phenotypes was stronger than L -siANLN. UTMD-siANLN attenuated EZH2 expression in CC cells. The modulatory role of UTMD-siANLN on EMT- and apoptosis-related markers was reversed by EZH2 overexpression. UTMD can improve the efficiency of siANLN transfection into CC cells to induce suppression of CC cell malignant phenotypes, which may become a new target of gene therapy for CC.
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
·
2026
·
IF 18.1
Zhijian Zhu,Rui Zhang,Haoran Kang,Meiyuan Chen,Hengjun Huang,Jing Wang,Ling Guo,Yuxing Li,Wenjing Chen,Limin Meng,Ruisi Wang,Ling Li,Kong-Peng Lam,Shengli Xu,Xijun Ou
Heterogeneous nuclear ribonucleoproteins (hnRNP) are key regulators of gene expression, yet the physiological functions of the highly homologous hnRNP A1 and A2B1 in B cells remain unclear. Here, we conditionally delete Hnrnpa1 and Hnrnpa2b1 in mouse B cells and find that loss of hnRNP A1 and A2B1 compromises the germinal center (GC) reaction during T cell-dependent immune responses. Loss of hnRNP A1 and A2B1 impairs GC B cell proliferation and high-affinity antibody production. Mechanistically, hnRNP A1/A2B1 bind UAG-rich motifs in Ezh2 pre-mRNA to promote Ezh2 exon 14 inclusion, thereby preserving EZH2 catalytic activity; in their absence, Ezh2 exon 14-skipping produces a catalytically inactive EZH2 isoform ( Ezh2 Δ14) with diminished repression of the cell cycle inhibitor Cdkn1a . The resulting CDKN1A accumulation restricts B cell proliferation, while Cdkn1a deletion partially rescues the GC defects in B cells deficient for hnRNP A1 and A2B1. Our findings thus uncover an hnRNP A1/A2B1–EZH2–CDKN1A axis that integrates RNA splicing with epigenetic regulation of B cell immunity. hnRNPs are RNA-binding proteins previously reported to regulate B cell differentiation and proliferation. Here, the authors show that hnRNP A1 and A2B1 support the germinal center reaction by retaining catalytically active EZH2, which reduces the cell cycle inhibitor CDKN1A, thereby promoting B cell proliferation.
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Juan Zhan,JianHan Zhou,RunQiang Liu,ChaoChen Wu,YiHan Lai,Lin Jiang,Wei Wang,Meng Cheng,YiSen Shao
Objective : Tongue squamous cell carcinoma (TSCC) is characterized by high invasiveness and early lymph node metastasis, leading to a poor prognosis.Current surgical and chemoradiotherapy regimens often cause functional impairment, drug resistance, and other drawbacks. Thus, developing highly effective, low-toxicity treatments is a key research priority. Traditional Chinese medicine (TCM) offers unique advantages via multi-target synergistic effects, enabling innovative therapeutic approaches. Method : In this study, we developed Astragaloside IV-Brucea javanica oil nanoemulsion (AS/BJO-NEs) and characterized its stability, polydispersity, and pharmacokinetic profile. The effects of AS/BJO-NEs on TSCC cells were evaluated through a series of functional assays, including CCK-8 (viability), colony formation (proliferation), and scratch wound healing (migration). Both in vitro and in vivo experiments were performed to investigate whether its mechanism involves regulation of the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis. Results The optimized AS/BJO-NEs exhibited uniform spherical morphology at the nanoscale and demonstrated favorable stability. In both in vitro and in vivo models, AS/BJO-NEs significantly suppressed the malignant phenotype of TSCC cells. Mechanistic investigation further revealed that the anti-tumor effects of AS/BJO-NEs are mediated, at least in part, through targeting the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis, as confirmed by establishing stable MTFR2/HIF-1α knockdown and overexpression cell models. Conclusion : This study demonstrates that AS/BJO-NEs inhibit TSCC progression by targeting the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis. Our findings provide experimental evidence supporting the development of multi-target therapeutic strategies derived from traditional Chinese medicine for the treatment of TSCC.
✓ 已验证
DOI
PubMed
高影响因子
Cell Death & Disease
·
2026
·
IF 12.2
Qiu Quanpeng,Ding Yi,Han Jing,Guo Xiaolong,Zhang Jiaqi,Chen Yue,Xue Xinzhu,Hu Xiake,Yu Tianyu,Liu Gaixia,Zhang Haowei,Li Qixin,Li Xiang,She Junjun,Chen Yinnan
The malignant transition of colorectal cancer (CRC) is caused by the combined action of epigenetic dysregulation and genomic instability. It is well known that EZH2-directed H3K27me3 modification is one of the main contributors to tumorigenesis; however, how it affects the DNA mismatch repair (MMR) system and the genesis of extrachromosomal circular DNA (eccDNA) remains unknown. Here, we demonstrate that EZH2 epigenetically represses critical MMR genes, which results in genomic instability and abnormal eccDNA accumulation, ultimately accelerating CRC progression. On the molecular level, the H3K27me3 mark catalyzed by EZH2 is the main cause of the downregulation of MMR genes, which affects the stability of the genome and leads to an increase in eccDNA that makes the tumor more aggressive. Our study reveals an unprecedented role of EZH2 in controlling chromosomal instability and eccDNA production through the MMR pathway and offers a conceptual framework for the development of CRC-targeted epigenetic therapies.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 7.446
Cheng Wang,Lailiang Qu,Shang Li,Fucheng Yin,Limei Ji,Wan Peng,Heng Luo,Dehua Lu,Xingchen Liu,Xinye Chen,Lingyi Kong,Xiaobing Wang
PARP inhibitors have highly significant effects on BRCA mutant cells, allowing targeted therapy of triple-negative breast cancer (TNBC). However, some TBNC patients lack BRCA mutations. Recent studies have shown that EZH2 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and EZH2 inhibitors, and the most promising compound, 5a, showed good inhibitory activity against PARP-1 and EZH2 and good inhibitory effects on MDA-MB-231 (IC50 = 2.63 μM) and MDA-MB-468 (IC50 = 0.41 μM) cells with wild-type BRCA. Compared with that of olaparib, the growth inhibitory activities against these two cell types increased by approximately 15- and 80-fold, respectively, which was even more effective than the combination of olaparib and tazemetostat/GSK126. 5a can induce autophagy death of tumor cells and cause less damage to normal cells. Therefore, 5a, as a first-in-class dual PARP and EZH2 inhibitor, is a potential anticancer drug candidate for the treatment of TNBC.
✓ 已验证
DOI
PubMed
高影响因子
Cell Death & Disease
·
2021
·Vol. 12
·期 5
·1-15
·
IF 8.469
Xu Xing,Chen Jun,Li Yan,Yang Xiaojie,Wang Qing,Wen Yanjun,Yan Ming,Zhang Jianjun,Xu Qin,Wei Yan,Chen Wantao,Wang Xu
The histone methyltransferase EZH2 silences gene expression via H3 lysine 27 trimethylation and has been recognized as an important antitumour therapeutic target. However, the clinical application of existing EZH2 inhibitors is not satisfactory for the treatment of solid tumours. To discover novel strategies against head and neck squamous cell carcinoma (HNSCC), we performed genomics, metabolomics and RNA omics studies in HNSCC cells treated with EZH2 inhibitors. It was found that EZH2 inhibitors strongly induced the expression of genes in cholesterol synthesis. Through extensive drug screening we found that inhibition of squalene epoxidase (a key enzyme of endogenous cholesterol synthesis) synergistically increased the squalene content and enhanced the sensitivity of HNSCC cells to EZH2 inhibitors. Our findings provide an experimental and theoretical basis for the development of new combinations of EZH2 inhibitors to treat HNSCC.
研究领域:
肿瘤学
·
表观遗传学
·
药理学
·
代谢组学
·
基因组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-19
·
IF 16.6
Li Yatian,Gao Zhenyue,Wang Yuhong,Pang Bo,Zhang Binbin,Hu Ruxin,Wang Yuqing,Liu Chao,Zhang Xuebin,Yang Jingxuan,Mei Mei,Wang Yongzhi,Zhou Xuan,Li Min,Ren Yu
Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.
研究领域:
肿瘤学
·
分子生物学
·
癌症治疗
·
神经肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Kaijun Gu,Yu Tan,Sitong Li,Siyue Chen,Bing Fang,Kaili Lin,Yanmei Tang,Min Zhu
Maxillofacial bone defects exhibit intricate anatomy and irregular morphology, presenting challenges for effective treatment. This study aimed to address these challenges by developing an injectable bioactive composite microsphere, termed D-P-Ak (polydopamine-PLGA-akermanite), designed to fit within the defect site while minimizing injury. The D-P-Ak microspheres biodegraded gradually, releasing calcium, magnesium, and silicon ions, which, notably, not only directly stimulated the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) but also activated sensory nerve cells to secrete calcitonin gene-related peptide (CGRP), a key factor in bone repair. Moreover, the released CGRP enhanced the osteogenic differentiation of BMSCs through epigenetic methylation modification. Specifically, inhibition of EZH2 and enhancement of KDM6A reduced the trimethylation level of histone 3 at lysine 27 (H3K27), thereby activating the transcription of osteogenic genes such as Runx2 and Osx. The efficacy of the bioactive microspheres in bone repair is validated in a rat mandibular defect model, demonstrating that peripheral nerve response facilitates bone regeneration through epigenetic modification. These findings illuminated a novel strategy for constructing neuroactive osteo-inductive biomaterials with potential for further clinical applications.
研究领域:
生物材料
·
组织工程
·
表观遗传学
·
骨再生
·
神经生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）