Glucose homeostasis controls N-acetyltransferase 10-mediated ac4C modification of HK2 to drive gastric tumorigenesis.

Abstract

Rationale: Abnormal metabolic states contribute to a variety of diseases, including cancer. RNA modifications have diverse biological functions and are implicated in cancer development, including gastric cancer (GC). However, the direct relationship between glucose homeostasis and 4-acetylcytosine (ac4C) modification in GC remains unclear. Methods: The prognostic value of RNA acetyltransferase NAT10 expression was evaluated in a human GC cohort. Additionally, preoperative PET/CT data from GC patients and Micro-PET/CT imaging of mice were employed to assess the relationship between NAT10 and glucose metabolism. The biological role of NAT10 in GC was investigated through various experiments, including GC xenografts, organoids, and a conditional knockout (cKO) mouse model. The underlying mechanisms were examined using dot blotting, immunofluorescence staining, co-immunoprecipitation, and high-throughput sequencing, among other techniques. Results: Glucose deprivation activates the autophagy-lysosome pathway, leading to the degradation of NAT10 by enhancing its interaction with the sequestosome 1 (SQSTM1)/microtubule-associated protein 1 light chain 3 alpha (LC3) complex, ultimately resulting in a reduction of ac4C modification. Furthermore, the levels of ac4C and NAT10 are elevated in GC tissues and correlate with poor prognosis. A strong correlation exists between NAT10 levels and 18F-FDG uptake in GC patients. Furthermore, NAT10 drives glycolytic metabolism and gastric carcinogenesis in vitro and in vivo. Mechanistically, NAT10 stimulates ac4C modification at the intersection of the coding sequence (CDS) and 3' untranslated region (3'UTR) of hexokinase 2 (HK2) mRNA, enhancing its stability and activating the glycolytic pathway, thereby driving gastric tumorigenesis. Conclusion: Our findings highlight the critical crosstalk between glucose homeostasis and the ac4C epitranscriptome in gastric carcinogenesis. This finding offers a potential strategy of targeting NAT10/HK2 axis for the treatment of GC patients, especially those with highly active glucose metabolism.