NAT10 promotes cancer metastasis by modulating p300/CBP activity through chromatin-associated tRNA

Protein and RNA acetylation are crucial for development and cancer progression. NAT10 is the only known acetyltransferase responsible for N4-acetylcytidine (ac4C) modification of RNA. However, the mechanism by which NAT10 contributes to cancer progression remains unclear. Here, we show that NAT10 interacts with a mechanosensitive, metastasis-susceptibility protein complex at the nuclear pore. Loss of NAT10's acetylation activity significantly reduces lung metastasis in both allograft and genetically engineered mouse models of breast cancer. Unexpectedly, upon NAT10 knockout, loss of ac4C modification in chromatin-associated tRNAs disrupts p300/CBP function, resulting in genome-wide chromatin reorganization and altered expression of genes that recruit metastasis-promoting myeloid cells to the tumor microenvironment. These findings highlight a role for NAT10 in regulating enhancer activity in metastatic tumor cells and reveal its impact on tumor-immune interactions that contribute to metastatic progression.