Advanced Science
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2025
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IF 14.1
Yu-Juan Zhan,Chun-Miao Deng,Lin Tang,Shu-Jun Li,Tao-Yang Xu,Xian Wei,Xin-Yi Zhang,Can-Can Zheng,Li Deng,Cui Shao,Zhong-Min Ouyang,Alfred King-Yin Lam,Rong Zhang,Jun Liu,Xing-Yuan Shi,Zhen-Yu Pan,Wei Dai,Ming-Liang He,Simon Law,Xu Li,Xiao-Bing Chen,Cheng Zhou,Bin Li,Wen-Wen Xu
N-acetyltransferase 10 (NAT10)-catalyzed N4-acetylcytidine (ac4C) modification has been reported to drive tumor metastasis. Lysosomal dysregulation plays an important role in human diseases, but its function in esophageal cancer metastasis is unclear. It remains unknown whether NAT10 regulates lysosomal function, and the underlying mechanism and treatment strategy warrants investigation. Here, a novel role of NAT10 in inducing lysosomal acidification is revealed, and the clinical and biological significance of ATP6V0E1 in tumor metastasis is uncovered. Mechanistically, NAT10 promotes the translation efficiency of ATPase H + transporting V0 subunit e1 (ATP6V0E1) mRNA in an ac4C-dependent manner to facilitate ATP6V0E1 expression and vacuolar H + -ATPase (v-ATPase) activity, enhancing the lysosomal degradation of E-cadherin, ultimately accelerating tumor metastasis. Furthermore, G-749 is screened and identified as a novel NAT10 inhibitor capable of effectively impeding lysosomal acidification and tumor metastasis by disrupting the NAT10-Ubiquitin-specific Peptidase 39 (USP39) interaction. Overall, the results unveil a novel role of ac4C modifications in regulating lysosomal acidification and propose a potential strategy by targeting NAT10 to inhibit esophageal cancer metastasis.
研究领域:
癌症生物学
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分子生物学
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生物化学
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细胞生物学
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肿瘤生物学
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RNA修饰
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药理学
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PubMed
高影响因子
Clinics
·
2025
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IF 2.4
Shan Xu,Xuming Lin,Fengling Jia
Objective Retinoblastoma (RB) is a type of intraocular tumor in childhood with a high lethality rate. N4-acetylcytosine (ac 4 C) modification is known to regulate multiple cancers, which is mediated by the only known ac 4 C writer N-Acetyltransferase 10 (NAT10). In this study, the authors aimed to reveal the mechanism of RB progression regulated by ac 4 C modification. Method Phenotypically, dot blot assay and quantitative real-time PCR were used to detect the ac 4 C levels and NAT10 expression in clinical samples and RB cell lines. Then, NAT10 was knocked down to assess its effect on glycolysis. Mechanically, RNA immunoprecipitation assay, immunofluorescence assay, and dual luciferase report were used to explore the mRNA modified by NAT10-mediated ac 4 C modification. Mice xenograft model was used to determine the effect of NAT10 on tumor growth in vivo . Results The present results demonstrated that the levels of ac 4 C and NAT10 were increased in cancer tissues and RB cell lines. Furthermore, NAT10 knockdown inhibited the glycolysis in RB cell lines. Moreover, the authors revealed that NAT10 knockdown decreased the ac 4 C modification and mRNA stability of HK1, while the inhibition of glycolysis by NAT10 knockdown was reversed by HK1 overexpression. Finally, NAT10 knockdown relieved the growth of tumors in mice models. Conclusion The authors illustrated that NAT10 plays an important role in the progression of RB by regulating the ac 4 C modification on HK1 mRNA and affects its stability, which may provide a novel theoretical basis for the treatment of RB.
研究领域:
肿瘤学
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分子生物学
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医学遗传学
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PubMed
高影响因子
NanoImpact
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2025
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IF 5.5
Feng-Jie Shen,Wei-Nan Cao,Xue-Chun Han,Qiu-Yue Pan,Yuan Wang,Rong Zhang,Gang Wei,Jin-Kui Yang
Microplastics (MPs) are environmental pollutants with potential health risks. This study examined the effect of MPs on wound healing in both diabetic and non-diabetic mice. MPs exposure significantly delayed wound healing, particularly in diabetic mice, with reduced epidermal thickness and impaired collagen deposition. Mechanistically, MPs suppressed cell proliferation, angiogenesis, and increased apoptosis. Transcriptomic analysis identified dysregulation of critical wound healing pathways, especially those involved in inflammation, extracellular matrix remodeling, and lipid metabolism. Notably, the PI3K/AKT signaling pathway was inhibited. In vitro experiments using human dermal fibroblasts confirmed that MPs disrupted the PI3K/AKT pathway, reducing cell proliferation and migration. Further investigation revealed that MPs suppressed N -acetyltransferase 10 (NAT10) expression, leading to reduced ac4C-dependent stabilization of Fasn mRNA, which in turn diminished lipid synthesis and further inhibited the PI3K/AKT pathway. Our findings reveal a novel interaction between MPs and diabetes in impairing wound healing and suggest the NAT10-FASN-PI3K/AKT axis as a potential therapeutic target.
研究领域:
环境毒理学
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分子生物学
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皮肤科学
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内分泌学
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药理学
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细胞生物学
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PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 7
·1-17
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IF 8.1
Wang Yuying,Su Kunqi,Wang Chang,Deng Tao,Liu Xiaofeng,Sun Shiqi,Jiang Yang,Zhang Chunfeng,Xing Baocai,Du Xiaojuan
Chemotherapeutic efficacy is seriously impeded by chemoresistance in more than half of hepatocellular carcinoma (HCC) patients. However, the mechanisms involved in chemotherapy-induced upregulation of chemoresistant genes are not fully understood. Here, this study unravels a novel mechanism controlling nuclear acetyl-CoA production to activate the transcription of chemoresistant genes in HCC. NAT10 is upregulated in HCC tissues and its upregulation is correlated with poor prognosis of HCC patients. NAT10 is also upregulated in chemoresistant HCC cells. Targeting NAT10 increases the cytotoxicity of chemotherapy in HCC cells and mouse xenografts. Upon chemotherapy, NAT10 translocates from the nucleolus to the nucleus to activate the transcription of CYP2C9 and PIK3R1 . Additionally, nuclear acetyl-CoA is specifically upregulated by NAT10. Mechanistically, NAT10 binds with ACLY in the nucleus and acetylates ACLY at K468 to counteract the SQSTM1-mediated degradation upon chemotherapy. ACLY K468-Ac specifically accumulates in the nucleus and increases nuclear acetyl-CoA production to activate the transcription of CYP2C9 and PIK3R1 through enhancing H3K27ac. Importantly, K468 is required for nuclear localization of ACLY. Significantly, ACLY K468-Ac is upregulated in HCC tissues, and ablation of ACLY K468-Ac sensitizes HCC cells and mouse xenografts to chemotherapy. Collectively, these findings identify NAT10 as a novel chemoresistant driver and the blockage of NAT10-mediated ACLY K468-Ac possesses the potential to attenuate HCC chemoresistance.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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PubMed
高影响因子
Frontiers in Endocrinology
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2022
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IF 6.055
Jiayu Lin,Yuting Xiang,Jiana Huang,Haitao Zeng,Yanyan Zeng,Jiawen Liu,Taibao Wu,Qiqi Liang,Xiaoyan Liang,Jingjie Li,Chuanchuan Zhou
In vitro maturation (IVM) refers to the process of developing immature oocytes into the mature in vitro under the microenvironment analogous to follicle fluid. It is an important technique for patients with polycystic ovary syndrome and, especially, those young patients with the need of fertility preservation. However, as the mechanisms of oocyte maturation have not been fully understood yet, the cultivation efficiency of IVM is not satisfactory. It was confirmed in our previous study that oocyte maturation was impaired after N-acetyltransferase 10 (NAT10) knockdown (KD). In the present study, we further explored the transcriptome alteration of NAT10-depleted oocytes and found that O-GlcNAcase ( OGA ) was an important target gene for NAT10-mediated ac4C modification in oocyte maturation. NAT10 might regulate OGA stability and expression by suppressing its degradation. To find out whether the influence of NAT10-mediated ac4C on oocyte maturation was mediated by OGA , we further explored the role of OGA in IVM. After knocking down OGA of oocytes, oocyte maturation was inhibited. In addition, as oocytes matured, OGA expression increased and, conversely, O-linked N-acetylglucosamine (O-GlcNAc) level decreased. On the basis of NAT10 KD transcriptome and OGA KD transcriptome data, NAT10-mediated ac4C modification of OGA might play a role through G protein-coupled receptors, molecular transduction, nucleosome DNA binding, and other mechanisms in oocyte maturation. Rsph6a , Gm7788 , Gm41780 , Trpc7 , Gm29036 , and Gm47144 were potential downstream genes. In conclusion, NAT10 maintained the stability of OGA transcript by ac4C modification on it, thus positively regulating IVM. Moreover, our study revealed the regulation mechanisms of oocytes maturation and provided reference for improving IVM outcomes. At the same time, the interaction between mRNA ac4C modification and protein O-GlcNAc modification was found for the first time, which enriched the regulation network of oocyte maturation.
研究领域:
生殖生物学
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分子生物学
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细胞生物学
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高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2025
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IF 11.3
Run Ling,Xin Yin,Liyao Ma,Yan Zhang,Yidan Ma,Rufei Gao,Yanqing Geng,Xinyi Mu,Xuemei Chen,Fangfang Li,Junlin He
Decabromodiphenyl ethane (DBDPE) is a brominated flame retardant widely used for its high flame retardancy and low bioavailability. However, DBDPE exhibits bioaccumulative potential. The placental vasculature, critical for the exchange between maternal and fetal circulation, is susceptible to environmental factors. We aimed to understand the potential toxicity of DBDPE to the placental vasculature. Gestational CD-1 mice and human umbilical vein endothelial cells (HUVECs) were exposed to 0, 0.5, 5, 50 mg/kg·bw·day or 0, 6.25, 12.5, 25, 50 μmol/L DBDPE, respectively. DBDPE exposure impaired placental angiogenesis and inhibited the proliferation and invasion of HUVECs by activating the endothelial-to-mesenchymal transition (EndMT) through the TGF-β1/Smad pathway, in vivo and in vitro . DBDPE upregulated the transcription factor TWIST2 and mRNA acetyltransferase NAT10. Knockdown or overexpression of TWIST2 reversed the vascular dysfunction and EndMT mechanism. DBDPE facilitated the recruitment of NAT10 by TWIST2, promoting N4-acetylcytidine (ac4C) RNA modifications and stabilizing the TGF-β1 mRNA. NAT10 inhibition rescued the effects caused by DBDPE. These findings uncover molecular mechanisms linking DBDPE exposure to adverse pregnancy outcomes, highlighting potential risks to pregnant women.
研究领域:
毒理学
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生殖生物学
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分子生物学
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环境健康
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细胞生物学
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RNA修饰
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发育生物学
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高影响因子
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
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2025
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IF 7.4
Yunhong Zhang,Zhen Zhang,Xinkui Liu,Chu Chu,Xiaoyan Yu,Qiaoqiao Han,Wei Li,Tingting Zhang,Huiyan Zu,Nannan Fan,Ran Wei,Feifei Shi,Fang Li,Fei Xu,Bin Wang,Xia Li
BACKGROUND:Deep vein thrombosis (DVT) is a prevalent peripheral vascular disorder associated with abnormal epigenetic processes and altered gene expression in endothelial cells. Accumulating evidence has demonstrated that NAT10 (N-acetyltransferase 10)–mediated N4-acetylcytidine modification exerts unique roles in ferroptosis, but its roles are still elusive in DVT.METHODS:To explore the potential mechanism of NAT10 and ferroptosis on thrombogenesis, we used NAT10 and GPX4 (glutathione peroxidase 4) knockout mice as an in vivo model, and utilized techniques, such as RNA immunoprecipitation, acRIP-qPCR, N4-acetylcytidine Dot Blotting assay, and Western blotting, for detailed molecular analysis.RESULTS:GPX4 is a pivotal gene that suppresses ferroptosis. Utilizing endothelial cell–specific GPX4 conditional knockout mice (GPX4fl/flCdh5-Cre+), we proved that ferroptosis in endothelial cells promotes the formation of thrombosis. Previous evidence indicates that NAT10 overexpression induces ferroptosis and downregulates GPX4 expression. Here, we found that NAT10 expression was elevated in DVT mice, and silencing of NAT10 markedly attenuated ferroptosis both in vitro and in vivo. Furthermore, endothelial cell–specific knockout of NAT10 (NAT10fl/flCdh5-Cre+) demonstrated a reduction in endothelial ferroptosis, thereby inhibiting both the formation and progression of DVT. Mechanistic studies indicated that NAT10 facilitated the N4-acetylcytidine modification of HMOX1 (heme oxygenase 1), which enhanced its mRNA stability, leading to the accumulation of ferrous ions, and exacerbating endothelial dysfunction in DVT.CONCLUSIONS:Collectively, our data elucidate that downregulation of NAT10 mitigates endothelial ferroptosis and prevents DVT formation and progression by modulating HMOX1 expression, which offers a potential novel strategy for the prevention and treatment of thrombosis in DVT.
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Cell Death & Disease
·
2026
·Vol. 17
·期 1
·326
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IF 12.2
Xin Hu,Meiqi Feng,Chengjin Qi,Boran Li,Hongjuan He,Kai Li,Lu Chen,Boshu Ji,Haoran Yu,Yue Zhao,Tong Wu,Ruiheng Ma,Yuhao Dong,Yan Zhang,Qiong Wu
Investigating the epigenetic mechanisms underlying lung adenocarcinoma (LUAD) through the lens of N 4-acetylcytosine (ac4C) modification could innovate cancer treatment strategies and targets. We used biological information methods to analyze shared data, with a focus on studying N -acetyltransferase 10 (NAT10), which is the only known ac4C “writer” protein. Our analysis revealed a significant upregulation of NAT10 expression in LUAD, a finding that was corroborated by investigations in both LUAD cancer tissue samples and cell lines. Subsequently, we employed CRISPR/Cas9 technology to knock out the NAT10 gene and analyzed the resulting knockout cells using acRIP-seq and RNA-seq techniques. Our findings demonstrated different expressions of the genes C-X-C motif chemokine ligand 5 (CXCL5) and DEK proto-oncogene (DEK), and functional enrichment analysis indicated a strong association with the adhesion signaling pathway. Laboratory experiments revealed that NAT10 acts as an ac4C “writer,” promoting the acetylation of CXCL5 and DEK and thus preventing the degradation of their mRNAs. Moreover, NAT10 was found to significantly affect the number of metastases and tumor growth following the injection of cancer cells into the tail vein of mice. Our research data suggests that targeting NAT10 has the potential to serve as a diagnostic biomarker or prognostic target for developing anti-metastatic therapies aimed at disrupting the adhesion process.
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高影响因子
Odontology
·
2023
·
IF 2.5
Cui Zhao,Xu Yunhe,Wu Peng,Lu Ying,Tao Yongxin,Zhou Chuibing,Cui Ruting,Li Jingying,Han Rongpeng
Periodontal tissue regeneration engineering based on human periodontal ligament stem cells (hPDLSCs) provides a broad prospect for the treatment of periodontal disease. N-Acetyltransferase 10 (NAT10)-catalyzed non-histone acetylation is widely involved in physiological or pathophysiological processes. However, its function in hPDLSCs is still missing. hPDLSCs were isolated, purified, and cultured from extracted teeth. Surface markers were detected by flow cytometry. Osteogenic, adipogenic, and chondrogenic differentiation potential was detected by alizarin red staining (ARS), oil red O staining, and Alcian blue staining. Alkaline phosphatase (ALP) activity was assessed by ALP assay. Quantitative real-time PCR (qRT-PCR) and western blot were used to detect the expression of key molecules, such as NAT10, Vascular endothelial growth factor A (VEGFA), PI3K/AKT pathway, as well as bone markers (RUNX2, OCN, OPN). RNA-Binding Protein Immunoprecipitation PCR (RIP-PCR) was used to detect the N4-acetylcytidine (ac4C) mRNA level. Genes related to VEGFA were identified by bioinformatics analysis. NAT10 was highly expressed in the osteogenic differentiation process with enhanced ALP activity and osteogenic capability, and elevated expression of osteogenesis-related markers. The ac4C level and expression of VEGFA were obviously regulated by NAT10 and overexpression of VEGFA also had similar effects to NAT10. The phosphorylation level of PI3K and AKT was also elevated by overexpression of VEGFA. VEGFA could reverse the effects of NAT10 in hPDLSCs. NAT10 enhances the osteogenic development of hPDLSCs via regulation of the VEGFA-mediated PI3K/AKT signaling pathway by ac4C alteration.
研究领域:
干细胞生物学
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分子生物学
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再生医学
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牙科科学
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DOI
PubMed
高影响因子
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