目的探讨NAT10在肝癌中的临床意义与潜在作用机制。方法基于癌症基因组图谱(The Cancer Genome Atlas,TCGA)获得的50例正常和374例肿瘤样本,采用R 4.2.1处理所获数据。结果NAT10在肿瘤样本中的表达显著高于正常样本(P<0.001)。与NAT1...目的探讨NAT10在肝癌中的临床意义与潜在作用机制。方法基于癌症基因组图谱(The Cancer Genome Atlas,TCGA)获得的50例正常和374例肿瘤样本,采用R 4.2.1处理所获数据。结果NAT10在肿瘤样本中的表达显著高于正常样本(P<0.001)。与NAT10低表达患者比较,NAT10高表达患者预后较差(P<0.001)。Logistic回归分析结果表明,NAT10高表达与肝癌患者临床预后不良因素相关,NAT10高表达患者更易于进展到晚期。基因集富集分析(gene set enrichment analysis,GSEA)结果显示,NAT10高表达样本中,异生物质代谢、凝血、脂肪酸代谢等相关基因特征均有差异富集。蛋白互作分析结果显示,NAT10可能与IGF2、SST、MUC2、CHGA、AGR2等基因存在相互作用。结论NAT10在肝癌中高表达,且表达水平与肝癌的临床特征及患者生存率存在相关性。NAT10可能是一种潜在的肝癌预后生物学标志物。展开更多
Although a single nucleotide polymorphism for N-acetyltransferase 10(NAT10)has been identified in patients with early-onset stroke,the role of NAT10 in ischemic injury and the related underlying mechanisms remains elu...Although a single nucleotide polymorphism for N-acetyltransferase 10(NAT10)has been identified in patients with early-onset stroke,the role of NAT10 in ischemic injury and the related underlying mechanisms remains elusive.Here,we provide evidence that NAT10,the only known RNA N4-acetylcytidine(ac4C)modification“writer”,is increased in the damaged cortex of patients with acute ischemic stroke and the peri-infarct cortex of mice subjected to photothrombotic(PT)stroke.Pharmacological inhibition of NAT10 with remodelin on Days 3–7 post-stroke or astrocytic depletion of NAT10 via targeted virus attenuates ischemia-induced infarction and improves functional recovery in PT mice.Mechanistically,NAT10 enhances ac4C acetylation of the inflammatory cytokine tissue inhibitor of metalloproteinase 1(Timp1)mRNA transcript,which increases TIMP1 expression and results in the accumulation of microtubule-associated protein 1 light chain 3(LC3)and progression of astrocyte autophagy.These findings demonstrate that NAT10 regulates astrocyte autophagy by targeting Timp1 ac4C after stroke.This study highlights the critical role of ac4C in the regulation of astrocyte autophagy and proposes a promising strategy to improve post-stroke outcomes via NAT10 inhibition.展开更多
Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acet...Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing(ac RIP-seq) and ribosome profiling sequencing(Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170(CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover,CEP170 overexpression promoted cellular proliferation and chromosomal instability(CIN) in MM.Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP170 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.展开更多
Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer develop...Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer development and prognosis has not yet been explored.This study aimed to examine the possible role of NAT10 in colon cancer.Methods:The expression levels ofNAT10were evaluated by immunohistochemical analyses with a colon cancer tissue microarray,and its prognostic value in patients was further analyzed.Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines.Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus.The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8(CCK-8),wound healing,Transwell,cell cycle,and ferroptosis assays.Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo.Dot blotting,acetylated RNA immunoprecipitation-qPCR,and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression.Results:NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines.This increased NAT10 expression was associated with shorter patient survival.Knockdown of NAT10 in two colon cancer cell lines(HT-29 and LoVo)impaired the proliferation,migration,invasion,tumor formation and metastasis of these cells,whereas overexpression of NAT10 promoted these abilities.Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1(FSP1)in HT-29 and LoVo cells.In these cells,FSP1 mRNA was found to be modified by ac4C acetylation,and this epigenetic modification was associated with the inhibition of ferroptosis.Conclusions:Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis,suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.展开更多
文摘目的探讨NAT10在肝癌中的临床意义与潜在作用机制。方法基于癌症基因组图谱(The Cancer Genome Atlas,TCGA)获得的50例正常和374例肿瘤样本,采用R 4.2.1处理所获数据。结果NAT10在肿瘤样本中的表达显著高于正常样本(P<0.001)。与NAT10低表达患者比较,NAT10高表达患者预后较差(P<0.001)。Logistic回归分析结果表明,NAT10高表达与肝癌患者临床预后不良因素相关,NAT10高表达患者更易于进展到晚期。基因集富集分析(gene set enrichment analysis,GSEA)结果显示,NAT10高表达样本中,异生物质代谢、凝血、脂肪酸代谢等相关基因特征均有差异富集。蛋白互作分析结果显示,NAT10可能与IGF2、SST、MUC2、CHGA、AGR2等基因存在相互作用。结论NAT10在肝癌中高表达,且表达水平与肝癌的临床特征及患者生存率存在相关性。NAT10可能是一种潜在的肝癌预后生物学标志物。
基金supported by grants from the National Natural Science Foundation of China(32200818 to Ling Yang,82371243,82171234 and 81971041 to Zhiqiang Pan,82201391 to Qihui Wang,82104147 to Guangtian Wang)the Jiangsu Provincial Association of Science and Technology Youth Science and Technology Talent Recruitment Project(Ling Yang,China)+2 种基金the Jiangsu-Specially Appointed Professor Project,the Jiangsu Province 333 High-Level Talent Cultivation Project,Key Project of Natural Science Foundation of Jiangsu Education Department(22KJA320008 to Zhiqiang Pan,China)Jiangsu Training Program of Innovation and Entrepreneurship for Undergraduates(202310313014Z to Angrong Wu,China)the Starting Grants of Excellent Talents of Xuzhou Medical University(Ling Yang,China).
文摘Although a single nucleotide polymorphism for N-acetyltransferase 10(NAT10)has been identified in patients with early-onset stroke,the role of NAT10 in ischemic injury and the related underlying mechanisms remains elusive.Here,we provide evidence that NAT10,the only known RNA N4-acetylcytidine(ac4C)modification“writer”,is increased in the damaged cortex of patients with acute ischemic stroke and the peri-infarct cortex of mice subjected to photothrombotic(PT)stroke.Pharmacological inhibition of NAT10 with remodelin on Days 3–7 post-stroke or astrocytic depletion of NAT10 via targeted virus attenuates ischemia-induced infarction and improves functional recovery in PT mice.Mechanistically,NAT10 enhances ac4C acetylation of the inflammatory cytokine tissue inhibitor of metalloproteinase 1(Timp1)mRNA transcript,which increases TIMP1 expression and results in the accumulation of microtubule-associated protein 1 light chain 3(LC3)and progression of astrocyte autophagy.These findings demonstrate that NAT10 regulates astrocyte autophagy by targeting Timp1 ac4C after stroke.This study highlights the critical role of ac4C in the regulation of astrocyte autophagy and proposes a promising strategy to improve post-stroke outcomes via NAT10 inhibition.
基金supported by National Key R&D Program of China (2020YFA0509400) (to Ye Yang)National Natural Science Foundation of China 81970196 (to Chunyan Gu) and 82073885 (to Ye Yang)+4 种基金Natural Science Foundation of Jiangsu Province (China) BK20200097 (to Chunyan Gu)National Natural Science Foundation of China 82073888 (to Hongbo Wang)the Science and Technology Support Program for Youth Innovation in Universities of Shandong (China) (2019KJM009) (to Hongbo Wang)Bohai rim Advanced Research Institute for Drug Discovery (China) (LX211011) (to Hongbo Wang)Jiangsu Postgraduate Research and Practice Innovation Program (China) KYCX21_1769 (to Rongfang Wei)。
文摘Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing(ac RIP-seq) and ribosome profiling sequencing(Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170(CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover,CEP170 overexpression promoted cellular proliferation and chromosomal instability(CIN) in MM.Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP170 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.
基金National Natural Science Foundation of China,Grant/Award Numbers:81902386,81972869,82002479The Natural Science Foundation of Jiangsu Province,Grant/Award Numbers:BK20211065,BK20200179+2 种基金China Postdoctoral Science Foundation,Grant/Award Number:2021M700547Youth Talent Science and Technology Project of Changzhou Health Commission,Grant/Award Number:QN202103The open fund of state key laboratory of Pharmaceutical Biotechnology,Nanjing University,China,Grant/Award Number:KF-202203。
文摘Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer development and prognosis has not yet been explored.This study aimed to examine the possible role of NAT10 in colon cancer.Methods:The expression levels ofNAT10were evaluated by immunohistochemical analyses with a colon cancer tissue microarray,and its prognostic value in patients was further analyzed.Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines.Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus.The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8(CCK-8),wound healing,Transwell,cell cycle,and ferroptosis assays.Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo.Dot blotting,acetylated RNA immunoprecipitation-qPCR,and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression.Results:NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines.This increased NAT10 expression was associated with shorter patient survival.Knockdown of NAT10 in two colon cancer cell lines(HT-29 and LoVo)impaired the proliferation,migration,invasion,tumor formation and metastasis of these cells,whereas overexpression of NAT10 promoted these abilities.Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1(FSP1)in HT-29 and LoVo cells.In these cells,FSP1 mRNA was found to be modified by ac4C acetylation,and this epigenetic modification was associated with the inhibition of ferroptosis.Conclusions:Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis,suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.
