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Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon responses via MYC/CDK2/DNMT1 pathway

ABSTRACT: Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon responses via MYC/CDK2/DNMT1 pathway

PROVIDER: PRJNA1150178 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30315310_1.fastq.gz	Fastqsanger.gz
	SRR30315310_2.fastq.gz	Fastqsanger.gz
	SRR30315311_1.fastq.gz	Fastqsanger.gz
	SRR30315311_2.fastq.gz	Fastqsanger.gz
	SRR30315312_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon responses via MYC/CDK2/DNMT1 pathway

Project description:Posttranscriptional modifications are deeply involved in cancer progression; however, there remains knowledge gap regarding the function and immune regulatory mechanism of newly discovered mRNA acetylation modification. Here, we discovered an unexpected role of N4-acetylcytidine (ac4C) RNA acetyltransferase NAT10 in reshaping the tumor immune microenvironment. By analyzing patients' data, we found that NAT10 was upregulated in tumor tissues and negatively correlated with immune cell infiltration and overall survival. Loss of tumoral NAT10 significantly stimulated tumor-specific cellular immune responses and suppressed tumor growth. Mechanistically, we identified MYC as a key downstream target of NAT10 via enhancing mRNA stability and translation efficiency. Inhibition of NAT10 blocked the MYC/CDK2/DNMT1 pathway, subsequently enhancing double-stranded RNAs (dsRNA) formation, which triggered type I interferon responses to enhance the in vivo response of tumor specific CD8+ T cells. More importantly, inhibition of NAT10 using either small molecule inhibitor (Remodelin) or PEI/PC7A/siNAT10 nanoparticles combined with PD-1 blockade synergistically enhanced the anti-tumor immune response and repressed tumor progression. Our findings uncovered the crucial role of tumor-intrinsic NAT10 in tumor immune microenvironment, representing a promising target for enhancing cancer immunotherapy.

2025-05-16 | PXD059596 | Pride

Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon responses via MYC/CDK2/DNMT1 pathway

Project description:Purpose:Posttranscriptional modifications are deeply involved in cancer progression; however, there remains knowledge gap regarding the function and immune regulatory mechanism of newly discovered mRNA acetylation modification.Methods: The expression of NAT10 in human tumor tissues was analyzed based on TCGA data. NAT10 knockout murine cell lines were generated to analyze the NAT10-associated tumor progression and anti-tumor immune response in tumor xenograft models. Immune cells and cytokines in TME were quantified by immunofluorescence, flow cytometry, quantitative reverse transcription-PCR, and ELISPOT assay. NAT10-associated differentially expressed genes were investigated in cancer cells and tissues with RNA-Seq. Results:Loss of tumoral NAT10 significantly stimulated tumor-specific cellular immune responses and suppressed tumor growth. Mechanistically, we identified MYC as a key downstream target of NAT10 via enhancing mRNA stability and translation efficiency. Inhibition of NAT10 blocked the MYC/CDK2/DNMT1 pathway, subsequently enhancing double-stranded RNAs (dsRNA) formation, which triggered type I interferon responses to enhance the in vivo response of tumor specific CD8+ T cells. Conclusions: Inhibition of NAT10 using either small molecule inhibitor (Remodelin) or PEI/PC7A/siNAT10 nanoparticles combined with PD-1 blockade synergistically enhanced the anti-tumor immune response and repressed tumor progression. Our findings uncovered the crucial role of tumor-intrinsic NAT10 in tumor immune microenvironment, representing a promising target for enhancing cancer immunotherapy.

2024-08-30 | GSE275283 | GEO

Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon responses via MYC/CDK2/DNMT1 pathway.

2024-12-30 | GSE285518 | GEO

Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon responses via MYC/CDK2/DNMT1 pathway.

Project description:Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon responses via MYC/CDK2/DNMT1 pathway.

| PRJNA1204289 | ENA

Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon responses via MYC/CDK2/DNMT1 pathway

Project description:label-free quantitative proteomics for WT and sgNAT10 TC1 cells. The LC-MS data were analyzed for data interpretation and protein identification against the Mus musculus database from Uniprot (downloaded on 01/02/2021, and including 88069 protein sequences), which is sourced from the protein database at https://www.uniprot.org/uniprot/?query=taxonomy:10090.

2025-05-16 | PXD059463 | Pride

NAT10 inhibition improves cellular phenotypes of Hutchinson-Gilford progeria syndrome by restoring the Transportin-1 pathway

Project description:In this experiment, we aim to examine the role of NAT10 inhibition in Hutchinson-Gilford progeria syndrome (HGPS), a rare but devastating premature ageing syndrome caused by a mutation in the LMNA gene. NAT10 inhibition improves HGPS cellular phenotypes by releasing Transportin-1 (TNPO1) from the cytoplasm, restoring the TNPO1 pathway and allowing hnRNPA1 and NUP153 nuclear import, TPR anchorage at the nuclear pore complexes and RanGTP gradient re-balancing. We have promoted NAT10 inhibition by two ways in normal or patient derived primary skin fibroblasts; the NAT10 inhibitor Remodelin, and an siRNA directly targeting NAT10 (siNAT10). In addition, we have also used an siRNA against TNPO1 and a combined siTNPO1 and siNAT10 treatment. This is a 2-factor design, with treatment (Remodelin vs untreated, or siNAT10 vs siCT) and condition (HGPS vs normal fibroblasts) as the two conditions. Transcriptional profiling was performed using HumanHT-12 v4 Expression BeadChip microarrays, and all conditions were run in triplicate.

2018-06-25 | E-MTAB-6651 | biostudies-arrayexpress

Targeting NAT10 enhances healthspan and lifespan in a mouse model of human accelerated aging syndrome.

Project description:Targeting NAT10 enhances healthspan and lifespan in a mouse model of human accelerated aging syndrome.

2018-03-22 | E-MTAB-6578 | biostudies-arrayexpress

CDK2 knockdown in prostate cancer cell lines

Project description:CDK2 is a cyclin-dependent kinase involved in regulating cell cycle progression. In prostate cancer, CDK2 has been shown to be associated with poor survival. We sought to identify key genes and molecular pathways regulated by CDK2 in prostate cancer. We therefore knocked down CDK2 using siRNA in PC3 and ResA cell lines, and performed RNA-seq.

2025-07-16 | GSE282801 | GEO

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells

Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. CDK2 shRNA in a tet repressor system was stably transfected in the IMR32 cell line. Time course analysis was performed in triplicate after induction of CDK2 shRNA at 5 time points.

2014-05-19 | E-GEOD-16480 | biostudies-arrayexpress

NAT10-ac4C axis promote renal fibrosis

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

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