NAT10 drives head and neck squamous cell carcinoma proliferation via ac4C modification of DDIT4 mRNA
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE314697 | GEO | 2025/12/24
REPOSITORIES: GEO
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Project description:NAT10 drives head and neck squamous cell carcinoma proliferation via ac4C modification of DDIT4 mRNA
| PRJNA1392468 | ENA
Project description:In our study, we aimed to identify the pathways and genes closely related to DVT. Through proteomic analysis, we found that the ferroptosis signaling pathway showed differential expression, and we also discovered that NAT10 (a key acetyltransferase modified by ac4C) was significantly overexpressed in DVT mice. Based on this discovery, we further investigated the downstream genes regulated by NAT10. We found that NAT10 enhances the stability of HMOX1 through ac4C modification, which results in iron overload and lipid peroxides, thereby forming a positive feedback loop that exacerbates DVT.
2026-01-26 | PXD067933 | Pride
Project description:We performedacRIP-seq between control CRC cells and CRC cells with NAT10 knockdown to identify NAT10 mediates mRNA ac4C modification
2022-08-19 | GSE202826 | GEO
Project description:Hepatocellular carcinoma (HCC) is characterized by high morbidity and mortality, withlimited effective treatment options. NAT10 is the only known acetyltransferase formRNA ac4C modification and is recognized as a biomarker for HCC, promoting itsprogression. However, the critical role of NAT10 in hepatocarcinogenesis remains tobe fully elucidated, and the identification of suitable small-molecule inhibitors targetingNAT10 is of great interest. Here, we report that NAT10 promotes HCC progression bystabilizing SMAD3 mRNA through ac4C modification. Clinically, NAT10 is highlyexpressed in HCC tissues and is significantly associated with poor prognosis.Functionally, NAT10 downregulation inhibits HCC cell proliferation, invasion, andepithelial-mesenchymal transition (EMT), while promoting anoikis in vitro.Additionally, NAT10 depletion significantly impairs tumor growth, metastasis, andhepatocarcinogenesis in vivo. Mechanistically, NAT10 enhances oncogene SMAD3mRNA stability via ac4C modification, thereby activating TGF-β signaling pathway.We also identify a novel small-molecule inhibitor, NAT10-2023, which effectivelyblocks NAT10 activity. Notably, NAT10-2023 treatment significantly reducesintracellular RNA ac4C modification levels and disrupts NAT10-RNA interactions,leading to suppressed tumor progression. Overall, NAT10 drives HCC progression viaSMAD3 mRNA stability regulation and NAT10-2023 could be a promising therapeuticcandidate for targeting NAT10 in cancer treatment.
2026-05-18 | GSE297856 | GEO
Project description:Hepatocellular carcinoma (HCC) is characterized by high morbidity and mortality, withlimited effective treatment options. NAT10 is the only known acetyltransferase formRNA ac4C modification and is recognized as a biomarker for HCC, promoting itsprogression. However, the critical role of NAT10 in hepatocarcinogenesis remains tobe fully elucidated, and the identification of suitable small-molecule inhibitors targetingNAT10 is of great interest. Here, we report that NAT10 promotes HCC progression bystabilizing SMAD3 mRNA through ac4C modification. Clinically, NAT10 is highlyexpressed in HCC tissues and is significantly associated with poor prognosis.Functionally, NAT10 downregulation inhibits HCC cell proliferation, invasion, andepithelial-mesenchymal transition (EMT), while promoting anoikis in vitro.Additionally, NAT10 depletion significantly impairs tumor growth, metastasis, andhepatocarcinogenesis in vivo. Mechanistically, NAT10 enhances oncogene SMAD3mRNA stability via ac4C modification, thereby activating TGF-β signaling pathway.We also identify a novel small-molecule inhibitor, NAT10-2023, which effectivelyblocks NAT10 activity. Notably, NAT10-2023 treatment significantly reducesintracellular RNA ac4C modification levels and disrupts NAT10-RNA interactions,leading to suppressed tumor progression. Overall, NAT10 drives HCC progression viaSMAD3 mRNA stability regulation and NAT10-2023 could be a promising therapeuticcandidate for targeting NAT10 in cancer treatment.
2026-05-18 | GSE297009 | GEO
Project description:The diverse RNA modifications play essential functions in gene expression regulation. Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here we revealed that the ac4C RNA acetyltransferase NAT10 is significantly upregulated in esophageal cancers (ESCA) and associated with poor ESCA prognosis. In addition, using cancer cell lines, xenograft tumor models, Nat10 conditional knockin and conditional knockout mice, in vivo ESCA tumorigenesis model and chemical inhibition approaches, we uncovered the critical physiological functions of NAT10 in promoting esophageal cancer tumorigenesis and progression in vitro and in vivo. Mechanistically, NAT10 depletion reduced the abundance of ac4C-modified tRNAs and significantly decreased the translation efficiencies of mRNAs enriched for ac4C-modified-tRNA decoded codons. We further identified EGFR as a key downstream target that facilitates NAT10’s oncogenic functions in promoting esophageal cancer progression. In terms of clinical significance, we demonstrated that NAT10 promotes esophageal cancer resistance to EGFR inhibitor gefitinib, and combination of NAT10 depletion and gefitinib treatment synergistically inhibits esophageal cancer progression in vitro and in vivo. Our data uncovered novel molecular mechanisms underlying esophageal cancer progression at the layer of mRNA translation control and provided molecular insights for development of effective cancer therapeutic strategies.
2023-02-16 | GSE225131 | GEO
Project description:RNA modification play vital roles in renal fibrosis. However, whether ac4C modification functions in renal fibrogenesis remains unknown. Here, we found that NAT10-ac4C axis plays pro—fibrotic role in kidney. ac4C RIP sequencing demonstrated NAT10-ac4C axis functions via regulating multiple master genes of exosome secretion in tubular epithelial cells. In summary, targeting NAT10-ac4C axis is a promising strategy for renal fibrosis.
2024-11-30 | GSE248203 | GEO
Project description:Vascular smooth muscle cells (VSMCs) phenotype switching is a pathological hallmark in various cardiovascular diseases. N4-acetylcytidine (ac4C), catalyzed by N-acetyltransferase 10 (NAT10), is well conserved in the enzymatic modification of RNA. NAT10-mediated ac4C acetylation is involved in various physiological and pathological processes, including cardiac remodeling. However, the biological functions and underlying regulatory mechanisms of mRNA ac4C modifications in vascular diseases remain elusive. By combining in vitro and in vivo vascular injury models, we identified NAT10 as a crucial protein involved in the promotion of postinjury neointima formation as well as VSMCs proliferation. The potential mechanisms of NAT10 in vascular neointima formation were clarified by RNA sequence (RNA-seq), acetylated mRNA immunoprecipitation sequence (acRIP-seq), and RNA binding protein immunoprecipitation sequence (RIP-seq). NAT10 and ac4C modification were upregulated in injured human and rodent arteries. Deletion of NAT10 in VSMCs effectively reduces postinjury neointima formation and VSMCs phenotype switching. Further RNA-seq, RIP-seq, and acRIP-seq revealed that NAT10, by its ac4C modification, directly interacts with genes, including integrin-β1 (ITGB1) and collagen type I alpha 2 chain (Col1a2) mRNAs. NAT10-mediated ac4C consequently increased ITGB1 mRNA stability and its downstream focal adhesion kinase (FAK) signaling, thereby directly influencing the proliferation of VSMCs and vascular remodeling. The regulation of NAT10 on VSMC phenotype is of translational significance because administration of remodelin, a NAT10 inhibitor, effectively prevents neointima formation by suppressing VSMCs proliferation and downregulating of ITGB1 expression and deactivating its FAK signaling. Our study reveals that NAT10 promotes vascular remodeling via mRNA Ac4c acetylation, which may be a promising therapeutic target against vascular remodeling.
2026-07-20 | GSE272001 | GEO
Project description:N4-acetylcytidine (ac4C) is a posttransciptional RNA modification regulating in various important bioprocess. However, the role in human cancer, especially lymph node metastasis, remains largely unknown. Here, we showed NAT10, as the only “writer” of ac4C mRNA modification, was highly expressed in HNSCC patients with lymph node metastasis. High NAT10 levels in lymph node of HNSCC patients predicted poor overall survival. Moreover, we found the high expression of NAT10 was positively upregulated by NRF1 transcription factor. Gain and loss-of-function displayed that NAT10 promoted cell metastasis in mice. Mechanistically, NAT10 induced ac4C modification of GLMP and stabilized its mRNA, which triggered the activation of MAPK/ERK signaling pathway. Lastly, the NAT10’s specific inhibitor Remodelin could inhibit HNSCC tumorigenesis via 4-NQO-induced murine tumor model and remodel the tumor microenvironment, including angiogenesis, CD8+ T cell and Treg recruitment. These results demonstrated that NAT10 promoted lymph node metastasis of HNSCC via ac4C-dependent stabilization of GLMP transcript, providing a potential epitranscriptomic-targeted therapeutic strategy for HNSCC.
2023-08-08 | GSE239900 | GEO
Project description:In our study, we investigated the role of the ac4C RNA modification enzyme NAT10 in Drosophila development. We found that knockdown of NAT10 led to a global reduction of ac4C levels on rRNA and impaired the assembly of the 40S ribosomal subunit and triggered a ribosome biogenesis stress response. This response was associated with increased cell apoptosis, cell competition, and reduced translational efficiency. Through genetic and transcriptomic analyses, we demonstrated that the developmental defects and transcriptional changes observed upon NAT10 knockdown were largely dependent on the upregulation of Xrp1, a key sensor of ribosome assembly stress. To explore the ac4C epitranscriptomic landscape and its functional implications in mRNA, we performed ac4C-RIP-seq in third instar larvae from three genotypes: Dats-GAL4/+ (control), Dats-GAL4 > UAS-NAT10-RNAi, and Dats-GAL4 > UAS-NAT10-RNAi Xrp1-RNAi. Our results revealed that ac4C modifications were widely distributed across the 5’UTR, CDS, and 3’UTR regions of mRNAs, with relatively higher enrichment in the 3’UTR.Integrated analysis of RNA-seq and ac4C-RIP-seq data revealed that the majority of differentially expressed genes upon NAT10 knockdown were not direct targets of ac4C modification. This indicates that the loss of ac4C on mRNAs has a limited direct impact on the transcriptome. Instead, the observed transcriptional alterations and developmental defects are primarily attributable to ribosome biogenesis stress.
2026-08-11 | GSE299446 | GEO