NAT10 promotes gastric cancer progression by enhancing the N4-acetylcytidine modification of TNC mRNA

Background: Gastric Cancer (GC) is a very aggressive malignant tumor of the digestive system. Previous studies have shown that N-acetyltransferase 10 (NAT10) can regulate the N4-acetylcytidine (ac4C) modification of downstream mRNAs through certain pathways to promote the progression of various tumors. However, reports on the regulatory effects of NAT10 on GC are rare. This study aimed to explore the potential mechanism by which NAT10 regulated GC progression.

Methods: Clinical samples were used to study the correlation between NAT10 expression and poor prognosis in patients with GC by univariate analysis and multivariate analysis. In vitro and in vivo assays were performed to assess the effects of NAT10 and Tenascin C (TNC) on the malignant biological behaviors of GC cells. Acetylated RNA immunoprecipitation Sequencing was conducted to explore the role of NAT10 in ac4C modification in GC. mRNA stability and translation efficiency assays were performed to investigate the effect of changes in NAT10 expression on its target TNC.

Results: Analysis of clinical samples revealed that NAT10 expression was abnormally elevated and positively correlated with TNC expression in GC, and increased NAT10 expression led to poor overall survival. In vitro and in vivo experiments revealed that high NAT10 expression promoted the invasive and proliferative capacity of GC cells. Rescue experiments suggested that TNC played an important role in the above process. Mechanistically, the acetylation-based RNA immunoprecipitation Sequencing and acetylated RNA immunoprecipitation qPCR results indicated that NAT10 regulated the level of ac4C modification by binding to specific regions in TNC mRNA, increasing mRNA stability and translation, upregulating TNC expression, further activating the TNC/Akt/TGF-β1 positive feedback loop.

Conclusions: In summary, our results reveal that NAT10 plays a critical role in GC development by affecting TNC mRNA stability and translation efficiency, which ultimately activates the TNC/Akt/TGF-β1 positive feedback loop. This study is expected to provide a novel target and theoretical basis for improving the diagnosis and treatment of GC.

Gastric cancer; N4-acetylcytidine; NAT10; TNC.