NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and resistance in cancer

Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here, we find that the ac4C RNA acetyltransferase NAT10 is significantly upregulated in esophageal cancers (ESCAs) and associated with poor ESCA prognosis. In addition, using ESCA cell lines and mouse models, we confirm the critical functions of NAT10 in promoting ESCA tumorigenesis and progression in vitro and in vivo. Mechanistically, NAT10 depletion reduces the abundance of ac4C-modified tRNAs and decreases the translation efficiencies of mRNAs enriched for ac4C-modified tRNA-decoded codons. We further identify EGFR as a key downstream target that facilitates NAT10's oncogenic functions. In terms of clinical significance, we demonstrate that NAT10 depletion and ge-fitinib treatment synergistically inhibit ESCA progression in vitro and in vivo. Our data indicate the mecha-nisms underlying ESCA progression at the layer of mRNA translation control and provide molecular insights for the development of effective cancer therapeutic strategies.

Automated summary

The upregulated expression of NAT10 is associated with poor prognosis in esophageal cancer. NAT10 plays a critical role in promoting esophageal cancer tumorigenesis and progression by regulating ac4C-modified tRNAs and mRNA translation. EGFR is identified as a downstream target of NAT10 that facilitates its oncogenic functions. Additionally, the depletion of NAT10 and the treatment with ge-fitinib synergistically inhibit esophageal cancer progression, suggesting potential therapeutic strategies.