Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer [mRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1275063 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33944520_1.fastq.gz | Fastqsanger.gz | |||
| SRR33944520_2.fastq.gz | Fastqsanger.gz | |||
| SRR33944524_1.fastq.gz | Fastqsanger.gz | |||
| SRR33944524_2.fastq.gz | Fastqsanger.gz |
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Project description:Lactylation, a metabolic stress-induced modification, plays a pivotal role in regulating diverse biological processes. Its involvement in perineural invasion (PNI) of pancreatic ductal adenocarcinoma (PDAC), however, has not been clearly defined. Our study demonstrates that patients with severe PNI exhibit significantly elevated levels of global lactylation and lactate, correlating with poorer prognosis. We identified NSUN2, a methyltransferase, as a crucial mediator of lactylation-driven PNI. Inhibition of lactylation or NSUN2 markedly reduced the neural infiltration capabilities of tumor cells. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC11 mRNA, enhanced their mRNA stability. Consistently, analyses using a KPC mouse model demonstrated that the lactylation of NSUN2/CDCP1/STC11 axis enhanced PNI through m5C modification. Our findings reveal that lactylation-driven NSUN2-mediated RNA m5C modification plays a pivotal role in promoting PNI and suggest that targeting NSUN2 could offer a promising therapeutic strategy for PDAC.
2025-06-15 | GSE299600 | GEO
Project description:Lactylation, a metabolic stress-induced modification, plays a pivotal role in regulating diverse biological processes. Its involvement in perineural invasion (PNI) of pancreatic ductal adenocarcinoma (PDAC), however, has not been clearly defined. Our study demonstrates that patients with severe PNI exhibit significantly elevated levels of global lactylation and lactate, correlating with poorer prognosis. We identified NSUN2, a methyltransferase, as a crucial mediator of lactylation-driven PNI. Inhibition of lactylation or NSUN2 markedly reduced the neural infiltration capabilities of tumor cells. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC11 mRNA, enhanced their mRNA stability. Consistently, analyses using a KPC mouse model demonstrated that the lactylation of NSUN2/CDCP1/STC11 axis enhanced PNI through m5C modification. Our findings reveal that lactylation-driven NSUN2-mediated RNA m5C modification plays a pivotal role in promoting PNI and suggest that targeting NSUN2 could offer a promising therapeutic strategy for PDAC.
2025-06-15 | GSE299599 | GEO
Project description:Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer, associated with aggressive tumor behavior and adverse patient outcomes. Despite its recognized clinical impact, the molecular mechanisms underlying PNI are not well understood. In this study, we isolated perineural invasion-associated cancer-associated fibroblasts (pCAFs), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared to non-perineural invasion-associated CAFs (npCAFs). Utilizing single-cell, high-throughput sequencing, and metabolomics, we identified a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAFs-derived lactate is absorbed by tumor cells, facilitating histone H3K18 lactylation. This epigenetic modification activates the transcription of neural invasion-associated genes such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, correlated with increased enzymatic activity and glycolytic flux. Targeting of GAPDH and lactylation modifications significantly inhibits neural invasion in a KPC mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Our findings provide critical insights into the role of pCAFs in the PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.
2025-03-19 | GSE290654 | GEO
Project description:Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer, associated with aggressive tumor behavior and adverse patient outcomes. Despite its recognized clinical impact, the molecular mechanisms underlying PNI are not well understood. In this study, we isolated perineural invasion-associated cancer-associated fibroblasts (pCAFs), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared to non-perineural invasion-associated CAFs (npCAFs). Utilizing single-cell, high-throughput sequencing, and metabolomics, we identified a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAFs-derived lactate is absorbed by tumor cells, facilitating histone H3K18 lactylation. This epigenetic modification activates the transcription of neural invasion-associated genes such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, correlated with increased enzymatic activity and glycolytic flux. Targeting of GAPDH and lactylation modifications significantly inhibits neural invasion in a KPC mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Our findings provide critical insights into the role of pCAFs in the PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.
2025-03-05 | GSE290845 | GEO
Project description:Background: As a widespread post-transcriptional RNA modification, N5-methylcytosine (m5C) is implicated in a variety of cellular responses and processes that regulate RNA metabolism. Despite this, a clear understanding of m5C modification’s role and mechanism in angiogenesis is still lacking. Methods: Single-cell RNA sequencing data was analyzed to determine expression of m5C methylase NSUN2. m5C levels were determined by mRNA isolation and anti-m5C dot blot in both hypoxia-induced endothelial cells (ECs) and laser-induced choroidal neovascularization (CNV). In addition, endothelial cell and endothelium‐specific NSUN2‐knockout mouse model were used to investigate the effect of NSUN2 silence on angiogenic phenotype. Genome-wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m5C-methylated RNA immunoprecipitation sequencing (m5C-meRIP-seq). CUT&Tag sequencing was performed to test the histone lactylation signal in the promoter region of NSUN2. Finally, AAV-mediated short hairpin RNAi knockdown of NSUN2 gene expression (AAV-shNSUN2) was constructed to investigate the effect of inhibiting CNV. Results: First, we discovered that m5C methylase NSUN2 expression level and mRNA m5C level were significantly higher in CNV-ECs than in normal ECs. NSUN2 knockdown in ECs inhibited proliferative, migration, and tube formation activities of ECs. Moreover, compared with EC NSUN2flox/flox mice, EC-specific NSUN2-deficient (EC NSUN2-/-) mice displayed less retinal vascular leakage after laser induction. Through multiomics analyses, we subsequently identified A-kinase anchoring protein 2 (AKAP2), a scaffolding protein which isolate Protein kinase A (PKA) to specific subcellular locations through binding to its regulatory subunit, as a downstream candidate target of NSUN2 in ECs. Overexpression of exogenous AKAP2 markedly reversed the inhibitory phenotypes in NSUN2-deficient ECs. Interestingly, laser induced NSUN2 up-regulation was driven by lactate-mediated lactylation on histone H3K18. In CNV models, AAV-mediated repression of NSUN2 modulated highly retinal vascular leakage and choroidal thickness. Conclusion: Overall, our findings indicate that NSUN2 is a novel therapeutic target for choroidal neovascularization.
2024-05-19 | GSE267662 | GEO
Project description:Background: As a widespread post-transcriptional RNA modification, N5-methylcytosine (m5C) is implicated in a variety of cellular responses and processes that regulate RNA metabolism. Despite this, a clear understanding of m5C modification’s role and mechanism in angiogenesis is still lacking. Methods: Single-cell RNA sequencing data was analyzed to determine expression of m5C methylase NSUN2. m5C levels were determined by mRNA isolation and anti-m5C dot blot in both hypoxia-induced endothelial cells (ECs) and laser-induced choroidal neovascularization (CNV). In addition, endothelial cell and endothelium‐specific NSUN2‐knockout mouse model were used to investigate the effect of NSUN2 silence on angiogenic phenotype. Genome-wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m5C-methylated RNA immunoprecipitation sequencing (m5C-meRIP-seq). CUT&Tag sequencing was performed to test the histone lactylation signal in the promoter region of NSUN2. Finally, AAV-mediated short hairpin RNAi knockdown of NSUN2 gene expression (AAV-shNSUN2) was constructed to investigate the effect of inhibiting CNV. Results: First, we discovered that m5C methylase NSUN2 expression level and mRNA m5C level were significantly higher in CNV-ECs than in normal ECs. NSUN2 knockdown in ECs inhibited proliferative, migration, and tube formation activities of ECs. Moreover, compared with EC NSUN2flox/flox mice, EC-specific NSUN2-deficient (EC NSUN2-/-) mice displayed less retinal vascular leakage after laser induction. Through multiomics analyses, we subsequently identified A-kinase anchoring protein 2 (AKAP2), a scaffolding protein which isolate Protein kinase A (PKA) to specific subcellular locations through binding to its regulatory subunit, as a downstream candidate target of NSUN2 in ECs. Overexpression of exogenous AKAP2 markedly reversed the inhibitory phenotypes in NSUN2-deficient ECs. Interestingly, laser induced NSUN2 up-regulation was driven by lactate-mediated lactylation on histone H3K18. In CNV models, AAV-mediated repression of NSUN2 modulated highly retinal vascular leakage and choroidal thickness. Conclusion: Overall, our findings indicate that NSUN2 is a novel therapeutic target for choroidal neovascularization.
2024-05-19 | GSE267661 | GEO
Project description:5-methylcytosine (m5C) modification ubiquitously occurs on mammalian mRNAs and plays important roles in multiple biological processes. Currently, the role of m5C in cancer initiation and progression is gaining more and more research attention, but the detailed mechanism remains unclear. As an m5C methyltransferase with unique mRNA catalytic activity, NSUN2 was found to be highly expressed in multiple cancers including gastric, bladder, gallbladder, and breast cancers, suggesting NSUN2 might exert oncogenic properties through affecting m5C levels in cancer cells. Therefore, to understand the potential roles of RNA m5C modification in tumorigenesis of cervical cancer, we established NSUN2 stable knockdown CaSki cell, and perform RNA-seq and RNA-BisSeq to figure out the possible pathway involved in cervical cancer development.
2021-09-24 | GSE184621 | GEO
Project description:Aims: Mammalian mRNA internal modification m6A has been suggested to be essential in the maintenance of cardiac homeostasis. The role of mRNA cytosine methylation (m5C) in the heart remains unexplored.Methods and results: In contrast with human normal heart, the expression of RNA cytosine methyltransferase NSun2 was found to be significantly elevated in the hypertrophied one. Consistently, NSun2 expression was increased in hypertrophic rat ventricular myocytes induced in vitro, as well as in TAC (transverse aortic constriction) developed hypertrophied murine heart. Cardiomyocyte-specific knockout of NSun2 (Myh6-CreERT2, NSun2 flox+/+) dramatically accelerated heart failure progression in TAC mice. RNA m5C immunoprecipitation followed by sequencing and MeRIP (methylation-specific RNA immunoprecipitation) revealed that NSun2 particularly methylates the mRNA of protein kinase A (PKA) catalytic subunit alpha (PRKACA). Polyribosome and dual luciferase reporter gene analysis further suggested that NSun2 promotes PRKACA translation via RNA methylation. In TAC hypertrophic cardiomyocytes, NSun2 ablation markedly dampened PKA signaling, as evidenced by reduced PKA activity and protein phosphorylation levels of PKA diverse substrates, impaired myocyte contraction and relaxation, and disturbed calcium transients. Cardiac-restricted overexpression of NSun2 via adeno-associated virus 9 (AAV9, NSun2 expression cassette driven by cTnT promoter) sensitized heart hypertrophic response, whereas administration of PKA inhibitor H89 successfully blocked this process, reiterating the importance of NSun2-PRKACA regulation in cardiac hypertrophic program.Conclusions: Our study showed that RNA methyltransferase NSun2 promotes PRKACA translation via RNA methylation, whereby achieving its modulation of PKA signaling within the cardiomyocyte. NSun2-PRKACA regulation is required for cardiac homeostasis maintenance and adaptation to hypertrophic stresses. These findings furnish us with novel understanding of heart function mediated by mRNA cytosine methylation in cardiac homeostasis.
2025-02-26 | GSE234445 | GEO
Project description:Purpose: The precise temporal and spatial regulation of N5-methylcytosine (m5C) RNA modification plays essential roles in RNA metabolism. Targeting m5C regulation in cancer cells may be a potential strategy for cancer therapy. Erianin is a natural product isolated from Dendrobium chrysotoxum Lindl. Howbeit, the in‐depth understanding of interaction between erianin and m5C modification remains indistinct. Methods: Natural product library screening was used to explore the effects of natural product monomers on uveal melanoma (UM) cells. Intraocular xenografts model was established to examine the effect of erianin. Immunoprecipitation mass spectrometry (IP-MS) and molecular docking analyses were performed to identify NSUN2 as the target of erianin. m5C-meRIP-seq and m5C-meRIP-qPCR analyses were performed to identify the functional target of NSUN2. Tube formation assay and CD31-PAS double staining were used to detect vasculogenic mimicry (VM) in UM. Results: Herein, we report the discovery of erianin as an effective inhibitor of uveal melanoma. Mechanistically, the targeted inhibition of NSUN2 function by erianin results in a decrease in the m5C modification and expression levels of CHAC1 in UM, thereby curtailing the formation of VM. Conclusions: Collectively, our data suggested that erianin significantly inhibited UM progression in vitro and in vivo. Our study unveils a novel therapeutic strategy for combating UM.
2024-12-10 | GSE280936 | GEO
Project description:NSUN2 mediated m5C modification regulates myocardial hypertrophy
| PRJNA981449 | ENA