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

ABSTRACT: 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.

INSTRUMENT(S): 6220 Time-of-Flight LC/MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung Cancer Cell

SUBMITTER: Wancheng Liu

LAB HEAD: Wancheng Liu

PROVIDER: PXD059463 | Pride | 2025-05-16

REPOSITORIES: Pride

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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.

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

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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

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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.

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Proteomic Analysis of olfactory cilia membranes

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Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A.

Project description:Peroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found that PPARA was expressed at relatively low levels in pancancers, and Kaplan-Meier analyses revealed that high PPARA protein expression was correlated with better survival of patients with colon cancer. In vitro experiments showed that fenofibrate regulated cell cycle distribution, promoted apoptosis, and suppressed cell proliferation and epithelial mesenchymal transition by activating PPARA. PPARA activation inhibited DNMT1 activity and abolished methylation-mediated CDKN2A repression. Downregulation of cyclin-CDK complexes led to the restoration of CDKN2A, which caused cell cycle arrest in the G1 phase via regulation of the CDKN2A/RB/E2F pathway. Finally, we demonstrated that fenofibrate administration inhibited tumor growth and DNMT1 activity in vivo. The PPARA agonist, fenofibrate, might serve as an applicable agent for epigenetic therapy of colon cancer patients.

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Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type, arr1, and AOE Transcriptomes

Project description:Purpose: The goals of this study are to identify the downstream regulated genes of ARR1. Methods: RNA was extracted from wild-type, arr1 single mutant, and AOE root explants at the nascent SAM formation stage. Library construction and RNA-Seq were performed by Biomarker Co. (www.biomarker.com.cn, Beijing, China). DESeq and the Q value were used to identify differentially transcribed genes (DTGs). Differential transcription was inferred by applying a false discovery rate threshold of 0.001 and the |log2 Ratio| ≥ 1. Functional categorization was inferred from a BLAST search of the non-redundant GenBank (http://www.ncbi.nlm.nih.gov/genbank/), KEGG Pathway (http://www.genome.jp/kegg/pathway.html), and UniProt protein databases (http://www.uniprot.org/), and was further analyzed by the Gene Ontology (http://geneontology.org/) method. Results: In the transcriptomes of arr1 vs. wild-type explants, we detected 177 up- and 260 downregulated DTGs, and in the AOE vs. wild-type transcriptomes, we detected 129 and 6 DTGs, respectively. The pathways involved in hormone signal transduction and indole alkaloid synthesis were well represented among the DTGs in arr1 vs. wild type. These DTGs also included genes involved in auxin transport and signaling, as well as IAA17, an Aux/IAA repressor gene, which was downregulated in arr1 root explants. Conclusions: Our study showed that IAA17 was downstream gene of ARR1 in root explants.

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