ac4C acetylation regulates mRNA stability and translation efficiency in osteosarcoma

Zhang, Wenjie; Gao, Jia; Fan, Lei; Wang, Juan; He, Bin; Wang, Yunhua; Zhang, Xiaotong; Mao, Hui

doi:10.1016/j.heliyon.2023.e17103

Cited by 5 publications

(2 citation statements)

References 33 publications

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“…Remodelin, as a novel small molecule, has been shown to reduce NAT10 activity 11 , thus preventing mRNA acetylation, and has been shown to be an effective treatment for various types of tumors 2 . In our previous study 12 , it was found that Remodelin can inhibit the growth of OS by suppressing the expression of NAT10 in osteosarcoma cells, but its specific mechanism of action remains to be elucidated.…”

Section: Introductionmentioning

confidence: 97%

Revealing the pharmacological effects of Remodelin against osteosarcoma based on network pharmacology, acRIP-seq and experimental validation

Gao,

Xu,

Wang

et al. 2024

Sci Rep

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Osteosarcoma (OS) is the most common primary malignant tumor of bone. Remodelin, an inhibitor of the N (4)-Acetylcytidine (ac4C) acetylation modifying enzyme N-acetyltransferase 10 (NAT10), has been shown to have therapeutic effects on cancer in several studies, and our previous studies have confirmed the inhibitory effect of Remodelin on OS cells, however, the mechanism of action has not yet been elucidated. We used network pharmacological analysis to quantify the therapeutic targets of Remodelin against OS. acRIP-seq and RNA-seq were performed to investigate the inhibitory activity of Remodelin on acetylation and its effect on the transcriptome after intervening in OS cells U2OS with Remodelin in vitro. Key target genes were deduced based on their pharmacological properties, combined with network pharmacology results and sequencing results. Finally, the deduced target genes were validated with vitro experiments. Network pharmacological analysis showed that 2291 OS-related target genes and 369 Remodelin-related target genes were obtained, and 116 overlapping genes were identified as Remodelin targets for OS treatment. Sequencing results showed that a total of 13,736 statistically significant ac4C modification peaks were detected by acRIP-seq, including 6938 hypoacetylation modifications and 6798 hyperacetylation modifications. A total of 2350 statistically significant mRNAs were detected by RNA-seq, of which 830 were up-regulated and 1520 were down-regulated. Association analyses identified a total of 382 genes that were Hypoacetylated-down, consistent with inhibition of mRNA acetylation and expression by Remodelin. Five genes, CASP3, ESR2, FGFR2, IGF1 and MAPK1, were identified as key therapeutic targets of Remodelin against OS. Finally, in vitro experiments, CCK-8 and qRT-PCR demonstrated that Remodelin indeed inhibited the proliferation of OS cells and reduced the expression of three genes: ESR2, IGF1, and MAPK1. In conclusion, ESR2, IGF1 and MAPK1 were identified as key therapeutic targets of Remodelin against OS. This reveals the target of Remodelin's pharmacological action on OS and provides new ideas for the treatment of OS.

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Section: Introductionmentioning

confidence: 97%

Revealing the pharmacological effects of Remodelin against osteosarcoma based on network pharmacology, acRIP-seq and experimental validation

Gao,

Xu,

Wang

et al. 2024

Sci Rep

Self Cite

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“… 14 , 15 It has been found that ac4C is widely present on mRNA wobble sites, which can help to maintain mRNA stability and improve translation efficiency. 16 To date, whether NAT10-mediated ac4C modification can regulate LSCC progression remains unclear. This study aims to reveal the role of NAT10-mediated ac4C modification in the malignant processes of LSCC cells.…”

Section: Introductionmentioning

confidence: 99%

NAT10 promotes the tumorigenesis and progression of laryngeal squamous cell carcinoma through ac4C modification of FOXM1 mRNA

Li,

Yang

et al. 2023

Cancer Biology & Therapy

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Laryngeal squamous cell carcinoma (LSCC), is a prevalent malignant tumor, belongs to the category of head and neck tumors. N-acetyltransferase 10 (NAT10) can alter mRNA stability through N4- acetylcytidine (ac4C) modification. This study aimed to make an investigation into the role of NAT10-mediated ac4C modification in the malignant processes of LSCC cells. The NAT10 expression in LSCC tissues and cells was detected RT-qPCR and western blot. The ac4C dot blot was performed to detect ac4C level. Besides, the cell viability, migration, and invasion abilities were detected by CCK-8 and transwell assays. AcRIP-qPCR was performed to measure the abundance of ac4C on FOXM1 mRNA. RIP and Luciferase reporter assays were performed to demonstrate the interaction between NAT10 and FOXM1. Finally, the xenograft model was established to explore the role of NAT10 in vivo. NAT1 levels were significantly increased in the LSCC tissues and cells. Knockdown of NAT10 could significantly suppress the proliferation, migration, and invasion of LSCC cells. Additionally, NAT10 recognized the ac4C-modified sites in the 3’-untranslated regions (3’ UTR) of forkhead box M1 (FOXM1) to enhance the ability of FOXM1 mRNA. Furthermore, FOXM1 overexpression reversed the suppressing effects of NAT10 knockdown on the proliferation, migration, and invasion of LSCC cells, according to the results of rescue assays. Finally, results of animal experiments showed that NAT10 promoted in vivo tumorigenesis of LSCC cells through upregulating FOXM1. Our current study demonstrated that NAT10-mediated ac4C modification of FOXM1 mRNA promoted the malignant processes of LSCC cells.

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Deciphering the role of lipid metabolism and acetylation in osteosarcoma: A comprehensive molecular analysis

Wen,

Zhang,

Zhang

et al. 2024

Environmental Toxicology

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Osteosarcoma, known for its rapid progression and high metastatic potential, poses significant challenges in adolescent oncology. This study delves into the roles of lipid metabolism and acetylation genes in the disease's pathogenesis. Utilizing gene set variation analysis, we examined 14 lipid metabolism‐related pathways in osteosarcoma patients, identifying significant variances in three pathways between metastatic and primary cases. Additionally, differences in four acetylation genes between these groups were observed. A comprehensive analysis pinpointed 62 lipid metabolism‐related genes, with 39 exhibiting significant correlations with acetylation genes, termed lipid metabolism acetylation (LMA) genes. Employing machine learning techniques like Lasso+RSF and GBM, we developed a predictive model for overall survival based on LMA genes. This model, with an average c‐index of 0.771, focuses on three key genes: CYP2C8, PAFAH2, and ACOX3, whose prognostic value was confirmed through survival and receiver operating characteristic curve analyses. Quantitative RT‐PCR results indicated higher expression levels of ACOX3 and PAFAH2 in OS cells (143B, HOS, MG63) than in osteoblasts (hFOB1.19), while CYP2C8 was lower in OS cells. Furthermore, drug sensitivity analysis through the pRRophetic algorithm suggested potential targeted therapies, revealing drugs with differential sensitivity based on LMA scores and varied treatment responses related to the expression of core genes. This study not only highlights the crucial role of lipid metabolism and acetylation in osteosarcoma but also offers a foundation for personalized treatment strategies, marking a notable advancement in combating this severe form of adolescent cancer.

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ac4C acetylation regulates mRNA stability and translation efficiency in osteosarcoma

Cited by 5 publications

References 33 publications

Revealing the pharmacological effects of Remodelin against osteosarcoma based on network pharmacology, acRIP-seq and experimental validation

Revealing the pharmacological effects of Remodelin against osteosarcoma based on network pharmacology, acRIP-seq and experimental validation

NAT10 promotes the tumorigenesis and progression of laryngeal squamous cell carcinoma through ac4C modification of FOXM1 mRNA

Deciphering the role of lipid metabolism and acetylation in osteosarcoma: A comprehensive molecular analysis

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